Amended Safety Assessment of Naturally-Sourced Claysas Used in Cosmetics

Status:Release Date:
Panel Meeting Date:

Draft Tentative Amended Report for Panel Review
September 1, 2022
September 26-27, 2022

The Expert Panel for Cosmetic Ingredient Safety members are: Chair, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito,
M.D.; David E. Cohen, M.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; Allan E. Rettie, Ph.D.; David Ross, Ph.D.;
Thomas J. Slaga, Ph.D.; Paul W. Snyder, D.V.M., Ph.D.; and Susan C. Tilton, Ph.D. Previous Panel member involved in thisassessment: Ronald C. Shank, Ph.D. The Cosmetic Ingredient Review (CIR) Executive Director is Bart Heldreth, Ph.D.
This safety assessment was prepared by Christina L. Burnett, Senior Scientific Analyst/ Writer, CIR.
© Cosmetic Ingredient Review
1620 L Street, NW, Suite 1200 ♢ Washington, DC 20036-4702 ♢ ph 202.331.0651
cirinfo@cir-safety.org

Distributed for Comment Only -- Do Not Cite or Quote

RE-REVIEW FLOW CHART

INGREDIENT/FAMILY ClaysMEETING _______ September 2022
Public Comment__________________________________________________

CIR

Expert Panel> 15 years
since last
reviewannounce
The Panel first considered at re-reviewof Silicates in June 2018. Several
reorganizations were done, and finally in
December 2019, a grouping of 8 Clayingredients was agreed upon for review
as a family. Six of the ingredients havebeen reviewed previously, 2 have not.

Re-Review

Rpt Status

New Data; orrequestOR
IJT 22 (Suppl 1):
37S-102S, 2003

Re-review to Panel

June 2018;
April 20192018 PRIORITY LIST
Are new data cause to reopen?

IDA had previously been issued April
2019 (as part of the larger group).

YES

NO

DRAFT AMENDEDREPORT
March 2022

DAR
Table

Table

IDA Notice
March 11, 2022

Draft TAR

IDA

TAR

Activated Clay (not previously reviewed)
was deleted from the report, so the total
number of ingredients is now 7.

IDA
DRAFT TENTATIVEAMENDED REPORT
Sept 2022

Table
Table

Tentative
Amended Report

60 day Public comment period

Draft FAR

Issue
TAR

DRAFT FINALAMENDED REPORT

Table
Table

PUBLISH

Final Amended
ReportDifferent Conclusion

Issue
FAR

Distributed for Comment Only -- Do Not Cite or Quote

Commitment & Credibility since 1976
Memorandum
To:
From:
Date:
Subject:

Expert Panel for Cosmetic Ingredient Safety Members and Liaisons
Christina L. Burnett, Senior Scientific Analyst/Writer, CIR
September 1, 2022
Amended Safety Assessment of Naturally-Sourced Clays as Used in Cosmetics

Enclosed is the Draft Tentative Amended Report on the Safety Assessment of Naturally-Sourced Clays as Used in Cosmetics. (It is
identified as report_Clays_092022 in the pdf document). At the March 2022 meeting, the Panel determined that the data wereinsufficient to support safety of the 7 clay ingredients. The additional data needs are:
• Particle size distribution (mean and range) on all ingredients, except Bentonite• Chronic inhalation data on all ingredients, except Attapulgite and Kaolin• Human dermal irritation and sensitization data at maximum use concentrations
Since the issuance of the Insufficient Data Announcement (IDA), CIR has received the following data:• Technical data and summary information on a clay product containing 19% Kaolin, 6% Montmorillonite, and 75% Illite(data1_Clays_092022)• HRIPT data on formulations containing up to 3.8% Bentonite and up to 14.498% Kaolin (data2_Clays_092022)• HRIPT on a formulation containing 3.5% Bentonite, clinical use data on a formulation containing 2% Bentonite and 2% Kaolin,
cumulative irritation and photoallergy data on a formulation containing 1.75% Bentonite, and human patch test on a formulation
containing 8% Bentonite (data3_Clays_092022)• Particle size distribution of Bentonite and Kaolin (data4_Clays_092022)• HRIPTs of formulations containing 7.5% Bentonite and 40% Kaolin (data5_Clays_092022)• In vitro irritation and sensitization data on a formulation containing 38% Montmorillonite (data6_Clays_092022)• Particle size information and dermal irritation and sensitization summary data on Hectorite (data7_Clays_092022)• Updated concentration of use data for the naturally-sourced clay ingredients (data8_Clays_092022)• In vitro ocular data and HRIPT data on a formulation containing 14.5% Kaolin (data9_Clays_092022)
These data have been incorporated into the report and are highlighted to aid the Panel’s review. (Please note, the Panel did notreceive any chronic inhalation data.) Some of the unpublished data contain information on illite (CAS No. 12173-60-3). According to
the Dictionary, illite refers to a group of clay-sized micas that have a higher lattice water content and lower potassium content than mica.
The US Geological Survey classifies illite as a clay; however, it uses the term “micaceous minerals” to describe it. Currently, there are 59
uses reported to the VCRP for illite and it is used at up to 0.02% in leave-on products (hair tonics and dressings) and at up to 3.8% in
rinse-off products (skin cleansing products). Does the Panel feel that this ingredient should be added to the naturally-sourced clays
report?
According to the updated concentration of use survey conducted by the Council, Kaolin has the highest concentration of use in a leave-on
formulation; it is used at up to 53.2% in manicuring preparing. This is approximately the same as the previously reported maximum use
concentration for Kaolin. The maximum use concentration for Bentonite in a leave-on product has decreased slightly. Currently it isreported to be used at up to 8% in skin care preparations. Previously, it was reported to be used at up to 15% in skin care preparations.
Maximum use concentrations in leave-on products for the remaining ingredients either decreased slightly or were not reported.

Also enclosed are comments received from Women’s Voices for the Earth (WVE), dated May 20, 2022
(WVEcomments_Clays_092022). WVE has provided some additional information about impurities of crystalline silica in Kaolinand Hectorite, which were identified from the websites of market products of several suppliers. WVE suggested caveats be madeto avoid the application of Kaolin and Hectorite in cosmetic formulations that may be incidentally inhaled. The information from
U.S. Silica Company on calcined kaolin was not included in the report. Based on the product description compared to current dataon method of manufacturing, it is not certain that this data refers to the ingredient Kaolin as found in the Dictionary. Likewise,
information from American Colloid Company on “Hectorite” was not included as the description of the product lists Bentonite as asynonym and gives the CAS # for Bentonite, not Hectorite. It cannot be ascertained to which ingredient this information actuallyrefers. The remaining impurities data have been incorporated into the report and highlighted to aid the Panel’s review.

__________________________________________________________________________________________
1620 L St NW, Suite 1200, Washington, DC 20036(Main) 202-331-0651(email) cirinfo@cir-safety.org (website) https://www.cir-safety.org

Distributed for Comment Only -- Do Not Cite or Quote

The WVE memo also includes some information relevant to nanoclay usage in cosmetics, which was identified from a report
written by a nanotechnology research company (StatNano). This report claimed that, based on the data covered by
Nanotechnology Products Database (NPD), 4% of the global nanoclay market is associated with cosmetic applications.
Specifically, nanoclay has been used as cosmetic additives for lipsticks, eyeliners, and toothpaste. It should be noted that suchreporting categories do not include any sprayable product type, thus mitigating the health concerns on incidental inhalation, which
was raised by WVE in their comments. However, it should also be noted the NPD database that presented the statistical data wasestablished by the same company (StatNano) that wrote the report. Therefore, it warrants further validation on the exact sharepercentage of cosmetics that use nanoclays in the global nanoclay market (e.g., the StatNano report stated 4% of the global
nanoclay market is shared by cosmetics). Nonetheless, the information regarding the application of nanoclay in relevant cosmetic
product categories has been incorporated into the report under the Cosmetic Use section for the Panel’s consideration.
The previously published report that included clay ingredients is attached for your use:
• 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, andZeolite (2003) [2003originalreport_Clays_092022]
Transcripts from all past meetings at which any of the clay ingredients named in this amended report were discussed, as well astranscripts from discussions of the current report, are included with this submission:• June 2018 through March 2022 – Minutes for the Panel’s deliberations since June 2018 when the re-review commenced[transcripts1-reopenedRR_Clays_092022]• September 1999 and February 2000 - 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, andZeolite [transcripts2-originalreport_Clays_092022]
Other supporting documents for this report package include a flow chart (flow_Clays_092022), 2022 VCRP raw data
(VCRP_Clays_092022), report history (history_Clays_092022), a search strategy (search_Clays_092022), and a data profile(dataprofile_Clays_092022).

A draft Abstract and Discussion have been included in this report version. The Panel should carefully consider and discuss thedata (or lack thereof), and issue a Tentative Amended Report with a safe, safe with qualifications, insufficient data, unsafe, or split
conclusion, and identify any additional items for inclusion in the Discussion.

-2-

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May 20, 2022

Re: Comments on the Safety Assessment of Clays as Used in Cosmetics
To the CIR,
These comments on the Safety Assessment of Clays are submitted on behalf of Women’s Voices for the
Earth.

1) Additional information on impurities found in kaolin and Hectorite are available
In the Composition/Impurities section of the Clays safety assessment, cristabolite (or crystalline silica) is
only mentioned as a potential impurity of Bentonite. However, crystalline silica is also a potential
impurity of both Kaolin and Hectorite.
KaolinThe following websites are from suppliers of kaolin - marketed specifically as kaolin products which aresuitable for use in cosmetics. The safety data sheets of each indicate that crystalline silica is a potential
impurity in the product.
https://www.crafters-choice.com/store-search.aspx?FBK=Kaolin“White Kaolin Clay is a cosmetic clay used in cold process soap, bath bombs and masks.”

https://www.crafters-choice.com/PDFs/ProductDocs/2700-SDS.pdf
Product Name: Crafter’s Choice™ White Kaolin Clay
“Depending on the type of handling and use (e.g. grinding, drying), airborne respirable crystalline silica may begenerated”

https://www.rusticescentuals.com/products/Kaolin-Clay.aspx“Suggested product uses: mineral makeup, cold process and M&P soaps, creams and lotions, bath bombs, bathsalts, shower gels and scrubs, facial masks and cleaners, and more.”

https://www.rusticescentuals.com/SDS/KaolinClaySDS.pdf“Product names: CLAY, KAOLIN, CHINA CLAY, HYDRATED KAOLIN
Minor component (2% or less) FREE RESPIRABLE SILICA (CAS# 14808-6-7”

https://www.ussilica.com/sites/default/files/2019-05/Anhydrous%20Kaolin%20OSHA%20GHS%20SDS2015.pdf

Distributed for Comment Only -- Do Not Cite or Quote“Product identifier: SNOW*TEX® 45 calcined kaolin; contains crystalline silica (quartz)(SNOW*TEX® is a registered trademark of U.S. Silica Company)
Recommended use of the chemical and restrictions on use: (non-exhaustive list) Adhesives, pharmaceuticals,
insecticides, glazes, paper, paints, refractories, sanitaryware, tableware, cosmetics, fertilizers, fiberglass,plastics, rubber, sealants, tiles.

Hectorite:
https://www.spectrumchemical.com/hectorite-h1406?section=16901
Hectorite, a rare white clay mineral, is found in the brown clay ghassoul which is used in making cosmetics and as amineral source for refined lithium metal.

https://www.spectrumchemical.com/media/sds/H1406_AGHS.pdf
Product Name: Hectorite
Components

CAS-NoWeight%Hectorite

12173-47-06

97-100

Crystalline Silica (Quartz)

14808-60-7

1-3

https://www.clays.org/wp-content/uploads/2020/08/SHCa-1.pdf
Trade name: Hectorite
Components

CAS-NoWeight%Hectorite

12173-47-06

97-100Quartz14808-60-7

1-3“Refer to the OSHA Respirable Crystalline Silica standards; 29CFR1910.1053, 1915.1053 and 1926.1053 for specificrequirements for use and handling.”

https://uwaterloo.ca/fine-arts/sites/ca.fine-arts/files/uploads/files/hectabrite_dp_03-11-16.pdf
Product identifier: Hectabrite DP
Synonyms: Smectite * Bentonite * Hectorite * Sodium-activated Bentonite
Constituents
Chemical name

CAS number%

CALCIUM CARBONATE
SMECTITE GROUP MINERALSQUARTZCRISTOBALITE

471-34-1
1318-93-0
14808-60-7
14464-46-1

<= 8
<= 2

Distributed for Comment Only -- Do Not Cite or Quote

This information on crystalline silica impurities in kaolin and Hectorite should be added theComposition/Impurities section of the Clays safety assessment.
At the March 2022 meeting, there was discussion of including a statement in the Clays Safety
Assessment that bentonite should not be used in cosmetic products which can be inhaled because of
the crystalline silica impurity. This statement should be extended to also include kaolin and Hectorite.
This is particularly a concern as kaolin has been identified as an ingredient in several airbrush makeup
products, which have the potential to be inhaled.

2.) Nanoclays are used in cosmetics.
In the Use section of the Safety Assessment under “Non-Cosmetic” there is a brief discussion of
nanoclays. This section ends with the claim “It is unknown if nanoclays are used in cosmetics.”
Fortunately, there is a relatively new report on nanoclays (from 2020) that details the variety of productuses for nanoclays around the world. It is now well-known that there are several cosmetic uses fornanoclays. The report (full text available) can be found here:
https://www.researchgate.net/publication/348959099_Nanoclaybased_Products_Across_Global_Markets_Applications_and_Properties
The report states that 4% of the global nanoclay market is used in cosmetics (Figure 4, P.10).
Given that nanoclays could have an even more significant impact on inhalation, given their small size,
the Safety Assessment should discuss the presence of nanoclays in cosmetics and the potential healthimpacts of their use. (And the statement that use of nanoclays in cosmetics is unknown should bedeleted from the assessment.)
Thank you for your consideration of these comments.
Sincerely,

Alexandra Scranton
Director of Science and Research

Distributed for Comment Only -- Do Not Cite or Quote

Clays History
2003– The CIR’s 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 in the IJT after the report was finalized by the Panel in 2000. Based on theavailable animal and clinical data available at that time, the Panel concluded that these ingredients are safe as cosmetic
ingredients in the practices of use and concentrations as described in the safety assessment.
April/May 2018 – Review of the available published literature since 2000 was conducted in accordance to CIR Procedures
regarding re-review of ingredients after ~15 years.
June 2018 - The Panel decided to re-open the 2003 Silicates report and add an additional 23 ingredients, which include 1
zeolite ingredient that was previously reviewed by the Panel and 5 zeolite ingredients that have not been reviewed by the
Panel.
Concentration of use survey on Activated Clay, Attapulgite, Bentonite, Fuller’s Earth, Hectorite, Kaolin, andMontmorillonite received.
December 2018 - The Panel issued an IDA for the 40 ingredients in the safety assessment. The additional data needed for thesafety assessment of these cosmetic ingredients are:•••

The range of particle sizes for all silica and silicate ingredients that are used in spray and powder formulations
Chemical characterization, composition, and impurities data for all ingredients, except Silica
Method of manufacturing and/or source data for all ingredients, except Silica and Hydrated Silica.

January 2019 – Unpublished data on Bentonite received.
April 2019 - The Panel tabled discussion on 40 ingredients for administrative reorganization. CIR staff will reorganize these
ingredients into 2 separate reports with the first report to be reviewed to include Silica, Hydrated Silica, and silicate
ingredients, with a focus on ingredients that are synthetically derived. The second report will be comprised of the ingredientsthat are determined to be naturally sourced (i.e. mined), including clay materials, zeolites, and any other ingredients in theabove list that are mined.
The data on all these ingredients are still considered insufficient to determine the conclusion on safety. The additional dataneeded for the two safety assessments of these cosmetic ingredients comprise:•••

The mean and range of particle sizes for all silica and silicate ingredients (and corresponding sizes of final
formulation particles) that are used in spray and powder formulations
Chemical characterization, composition, and impurities data for all ingredients, except Silica
Method of manufacturing and/or source data for all ingredients, except Silica and Hydrated Silica.

December 2019 - The Panel considered the proposed groupings of the 38 ingredients that had been previously removed fromthe Amended Safety Assessment on Silica and Hydrated Silica and a larger re-review package of silicate ingredients. The Panel
accepted the groupings proposed by CIR Staff, which will be presented in 3 separate reports at future Panel meetings. The
Panel also accepted the proposed addition of the ingredient, Clay, to the reviews. The groups are as follows:
Clays

Activated Clay
Attapulgite
Bentonite
Clay

Fuller’s Earth
Hectorite
KaolinMontmorillonite

Zeolites
Ammonium Silver Zeolite
Gold Zeolite
Silver Copper Zeolite

Titanium Zeolite
ZeoliteZinc Zeolite

Silicates
Aluminum Silicate
Aluminum Calcium Sodium Silicate
Aluminum Iron Silicates

Aluminum Iron Calcium Magnesium Germanium
Silicates
Aluminum Iron Calcium Magnesium Zirconium Silicates

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Ammonium Silver Zinc Aluminum Silicate
Calcium Silicate
Calcium Magnesium Silicate
Lithium Magnesium Silicate
Magnesium Aluminometasilicate
Magnesium Aluminum Silicate
Magnesium Silicate
Magnesium Trisilicate
Potassium Silicate
Pyrophyllite

Sodium Magnesium Silicate
Sodium Metasilicate
Sodium Magnesium Aluminum Silicate
Sodium Potassium Aluminum Silicate
Sodium Silver Aluminum Silicate
Sodium Silicate
Tromethamine Magnesium Aluminum Silicate
Zinc Silicate
Zirconium Silicate

April 2020 – Concentration of use survey on the ingredient Clay received.
March 2022 - The Panel issued an IDA for the 7 clay ingredients. The additional data needed to determine
safety for these cosmetic ingredients are:•Particle size distribution (mean and range) on all ingredients, except Bentonite•
Chronic inhalation data on all ingredients, except Attapulgite and Kaolin•
Human dermal irritation and sensitization data at maximum use concentrations
March-July 2022 – Unpublished data received on Bentonite, Hectorite, Kaolin, and Montmorillonite.

Case Reports

Retrospective/
Multicenter

X

ClinicalStudiesAnimalPhototoxicity

X

OcularIrritation

In Vitro

Human

AnimalDermalSensitization

In Vitro

Human

Animal

In Vitro

DermalIrritation

Inhalation

Oral

In Vitro
O
X

Carci

DermalGenotox

In Vivo

DART

Oral

Inhalation

Oral

XO

Repeated
Dose Tox

DermalX

Inhalation

XO

O
O
XO

O
O
O

Oral

O
XO

Acute Tox

Dermal

O
XO

ADME

X

O
O

Dermal Pen.

Montmorillonite

Composition/
Impurities

X
X
X
X
X
X

Method of Mfg

Attapulgite
Bentonite
Clay*
Fuller’s Earth
Hectorite
KaolinToxicokinetic

Old Rpt

New Rpt

Use

DermalDistributed for Comment Only -- Do Not Cite or Quote
Clays Data Profile – September 2022, Christina Burnett

O
X

O
O

X
O
X
O

X
X

O
X
O
X

X
X

O
X

O
X
X

O
X

O
X

X

*Not previously reviewed“X” indicates that new data were available in this category for the ingredient; “O” indicates that data from the original assessment were available

1

X

X
X

X
X

X

X

O
X

O

X

O

Distributed for Comment Only -- Do Not Cite or Quote

Clays
IngredientCAS #PubMed

FDA

HPVIS

NIOSH

NTIS

NTP

FEMA

EU

ECHA

ECETOC

SIDS

SCCS

AICIS

FAO

WHO

Web

Attapulgite

12174-11-7

√

√

√

√

√

√

√

√

√

√

√

√

√

√

√

√

Bentonite
Clay
Fuller’s Earth
Hectorite

1337-76-4
1302-78-9
53801-44-8
8031-18-3
12173-47-6

√
√
√
√

√
√
√
√

√
√
√
√

√
√
√
√

√
√
√
√

√
√
√
√

√
√
√
√

√
√
√
√

√
√
√
√

√
√
√
√

√
√
√
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√
√
√
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√
√
√
√

√
√
√
√

√
√
√
√

√
√
√
√

KaolinMontmorillonite

68084-71-9
1332-58-7
1318-93-0

√
√

√
√

√
√

√
√

√
√

√
√

√
√

√
√

√
√

√
√

√
√

√
√

√
√

√
√

√
√

√
√

Search Strategy (from 1999 for re-review)
Search Strategy: Re-review ingredients limited time frame from 2000-2018, except where noted
PubMedActivated Clay (no time frame limits) – 383 hits (0 relevant)Attapulgite – 231 hits, limited with toxicity = 13 hits (3 relevant), limited with irritation = 0 hits, limited with sensitization = 0 hits, limited with dermal = 0 hits
Bentonite – 2155 hits, limited with toxicity = 161 hits, limited with irritation = 3 hits (1 relevant), limited with sensitization = 0 hits, limited with dermal = 7 hits (1 relevant)Clay (no time frame limits) – 19,404 hits overly broad term
Fuller’s Earth – 50 hits (12 relevant)Hectorite – 89 hits (0 relevant)Kaolin – 1964 hits, limited with toxicity = 160 hits (4 relevant), limited with irritation = 2 hits (0 relevant), limited with sensitization = 17 hits (0 relevant), limited with dermal = 1
hit (0 relevant)Montmorillonite – 3385 hits, limited with toxicity = 214 hits (8 relevant), limited with irritation = 6 hits (1 relevant), limited with sensitization = 0 hits, limited with dermal = 8 hits
(1 relevant)Typical Search Terms (this is informational – not for inclusion for search strategy that goes to the Panel)

INCI names
CAS numbers
chemical/technical names
additional terms will be used as appropriate

updated July 2022

Distributed for Comment Only -- Do Not Cite or Quote

LINKS
Search Engines
 Pubmed - http://www.ncbi.nlm.nih.gov/pubmed- appropriate qualifiers are used as necessary- search results are reviewed to identify relevant documents• Connected Papers - https://www.connectedpapers.com/
Pertinent Websites
 wINCI - http://webdictionary.personalcarecouncil.org
 FDA databases http://www.ecfr.gov/cgi-bin/ECFR?page=browse
 FDA search databases: http://www.fda.gov/ForIndustry/FDABasicsforIndustry/ucm234631.htm;,
 Substances Added to Food (formerly, EAFUS): https://www.fda.gov/food/food-additives-petitions/substances-added-food-formerly-eafus
 GRAS listing: http://www.fda.gov/food/ingredientspackaginglabeling/gras/default.htm
 SCOGS database: http://www.fda.gov/food/ingredientspackaginglabeling/gras/scogs/ucm2006852.htm
 Indirect Food Additives: http://www.accessdata.fda.gov/scripts/fdcc/?set=IndirectAdditives
 Drug Approvals and Database: http://www.fda.gov/Drugs/InformationOnDrugs/default.htm
 FDA Orange Book: https://www.fda.gov/Drugs/InformationOnDrugs/ucm129662.htm
(inactive ingredients approved for drugs: http://www.accessdata.fda.gov/scripts/cder/iig/
 HPVIS (EPA High-Production Volume Info Systems) - https://iaspub.epa.gov/oppthpv/public_search.html_page
 NIOSH (National Institute for Occupational Safety and Health) - http://www.cdc.gov/niosh/ NTIS (National Technical Information Service) - http://www.ntis.gov/
o technical reports search page: https://ntrl.ntis.gov/NTRL/ NTP (National Toxicology Program ) - http://ntp.niehs.nih.gov/
 Office of Dietary Supplements https://ods.od.nih.gov/
 FEMA (Flavor & Extract Manufacturers Association) GRAS: https://www.femaflavor.org/fema-gras EU CosIng database: http://ec.europa.eu/growth/tools-databases/cosing/ ECHA (European Chemicals Agency – REACH dossiers) – http://echa.europa.eu/information-on-chemicals;jsessionid=A978100B4E4CC39C78C93A851EB3E3C7.live1
 ECETOC (European Centre for Ecotoxicology and Toxicology of Chemicals) - http://www.ecetoc.org
 European Medicines Agency (EMA) - http://www.ema.europa.eu/ema/ OECD SIDS (Organisation for Economic Co-operation and Development Screening Info Data Sets)- http://webnet.oecd.org/hpv/ui/Search.aspx
 SCCS (Scientific Committee for Consumer Safety) opinions: http://ec.europa.eu/health/scientific_committees/consumer_safety/opinions/index_en.htm

AICIS (Australian Industrial Chemicals Introduction Scheme)- https://www.industrialchemicals.gov.au/ International Programme on Chemical Safety http://www.inchem.org/
 FAO (Food and Agriculture Organization of the United Nations) - http://www.fao.org/food/food-safety-quality/scientific-advice/jecfa/jecfa-additives/en/
 WHO (World Health Organization) technical reports - http://www.who.int/biologicals/technical_report_series/en/ www.google.com - a general Google search should be performed for additional background information, to identify references that are available, and for other general
information

updated July 2022

Distributed for Comment Only -- Do Not Cite or Quote

Clays – Expert Panel for Cosmetic Ingredient Safety Meeting Transcripts

JUNE 2018 PANEL MEETING – RE-REVIEW
Belsito’s Team Meeting – June 4, 2018
DR. BELSITO: Silicates. This was also part of Wave 2. And this is a re-review with a question of add-ons,correct?
MS. BURNETT: Correct. And I handed out at the table this morning to help clarify what add-ons are where,
hopefully to help your discussion.
DR. BELSITO: Yes, I didn’t see that. I said combined them all, add in the new ones. We need to take a look
regardless. Usage has increased astronomically for many, and we need a sense of concentration of use, regardless ofwhat we decide to do. That was my analysis.
DR. LIEBLER: Yeah, I said reopen to add all the new ingredients. This is a chemically heterogeneous group, so
the new ingredients easily belong. That’s the benefit of the dog’s breakfast, by the way.
However, their properties aren’t significantly different, and existing data covers the entire group. No need for new
data, we can affirm the previous conclusion.
DR. BELSITO: I don’t know that we can confirm it until we get a sense of concentration of use.
DR. LIEBLER: Fine.
DR. EISENMANN: And the report is not correct. The concentration of use survey has not been started on silica
and hydrated silica. Those weren’t included in the list they gave me. And I don’t expect that to be -- if I get it
started -- those are high use ingredients, so it’s going to take at least -DR. BELSITO: That’s fine.
DR. EISENMANN: So, don’t expect to see this until December.
DR. BELSITO: Oh, I wanted to see it in September.
DR. EISENMANN: Well -DR. BELSITO: I’m teasing you Carol.
DR. EISENMANN: -- I doubt we’ll get to those that quick.
DR. BELSITO: No, I mean, that’s fine. I just thought that we could open, merge them all, add in the new ones.
But the use has increased astronomically, which is part of the reason to look at it again anyway.
DR. EISENMANN: I was a little concerned about -- see I think this isn’t chemistry that drives the toxicity of these
ingredients, it’s more structure. And it wasn’t really addressed at all in this report. There is a discussion that’s in
the silica report about amorphous versus crystalline. I don’t know, that’s part of my concern about combining this,that that might get lost.
DR. BELSITO: Okay, so, run that by me again. Your concern here is not the chemistry it’s the structure.
DR. EISENMANN: It’s the physical structure of these compounds.
DR. BELSITO: Dan, you need to address that because that’s above my head.

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DR. EISENMANN: Right, and I’m not an expert in it either. I just know that was a big issue in the report, and thereport hasn’t been published, so I’m a little concerned about -MS. BURNETT: Because that report hasn’t been published, pretty much the entirety -- it will be reorganized intocurrent format. But the bulk of the data will still be there. It’s not going to be like the published paper re-review,
where we italicize it, and then it doesn’t get published. This will go directly into this paper; and so, it will be like a,
you know, silica 2.0 version for the panel to review.
DR. BELSITO: Right. How come that report wasn’t published?
MS. FIUME: I don’t know. It may have been internal. It may have been journal, I’m not sure. But it did needsome reorganization. So, it’ll be incorporated in here and all of the information will get published.
DR. BERGFELD: With the mention of the structural differences, is it possible to reorganize according to thestructure?
DR. BELSITO: Anything is possible.
DR. LIEBLER: To the extent that they’re all structurally characterized. I suppose. The structure issue, as opposedto the chemical substance issue, Don, is like these crystalline silica versus amorphous silica. Chemically, in achemical composition sense, they’re about the same. In the way that the structure is, they’re very different. And
because the structure is different, they interact with biological components differently.
MS. BURNETT: I’m still reading and trying to understand the original report. But as I have read the physicalproperties and method of manufacture section, we have clearly stated that the cosmetic silica is amorphous not
crystalline.
So as far as I understand, the data that is in this report is only on the amorphous silica. And there are like different
names within the amorphous silica, but we go by the INCI names. So, if the amorphous silica is the silica, that’s
what the report is on.
DR. LIEBLER: I use that as an example of a structure difference for Don to explain, I think, what Carol was
pointing out. I don’t know how these partition into crystalline or amorphous. If the data you have so far says these
are all amorphous silicates, then that’s what they are. And I guess we’re going to need more data to make decisions
about grouping them.
MS. BURNETT: Okay.
DR. LIEBLER: Are you going to think about subgrouping them? I don’t know if we are. I don’t know if we needto.
DR. KLAASSEN: Here we do have, in contrast to one of the chemicals we were talking about this morning, youknow, It is well known -- and as you know -- that some silica compounds can cause silicosis, which is a real lungdisease. And so, we need to make sure that we know which ones might cause silicosis and which ones don’t cause
silicosis.
DR. BELSITO: But isn’t that the point Christina was making with the amorphous versus crystalline? Because it’s
the crystalline ones that cause silicosis.
DR. KLAASSEN: But that’s what I’m saying; we need to make sure that all of these that we have here -- or what is
known about it to make -- we need to make sure that these are all the amorphous. And how strong is the data, firstof all, that it has to be an amorphous compared to a crystalline, et cetera; which I don’t know offhand.

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MS. FIUME: I do know, looking at the minutes, PDF Page 54, maybe that’s the 2009 review; where the Paneldetermined that silicosis is not an issue since crystalline silica is not an ingredient used in cosmetics. So, that’s what
was discussed at that time, that it’s not crystalline.
DR. BELSITO: So, as you go through the add-ons, et cetera, just make sure that what we’re talking about isamorphous. Anything else?
Marks’ Team Meeting – June 4, 2018
DR. MARKS: I know. Silicates. Let’s see, I have silicates are the next.
DR. SHANK: That’s what I have.
DR. MARKS: And this is silicate related ingredients re-review.
MS. BURNETT: This morning, to help in the discussion -- I apologize, when I wrote this report, I didn’t put in atable summarizing which ingredients were the existing ingredients, which were the previously reviewed ingredients,
and which were the brand new potential add-ons.
It was clear to me because I had my table, but I didn’t include it in the report. I handed that out this morning to help
you see which was which; so that when you’re talking you know which ingredients -DR. SHANK: Thank you. Thank you.
DR. ANSELL: Do you have an extra copy of that by any chance?
MS. BURNETT: I don’t have any extra copies.
DR. SHANK: Here, I’ll give you mine.
DR. ANSELL: Can you part with it?
DR. SHANK: Sure. Who needs it?
MS. BURNETT: Oh, she has electronic.
DR. SHANK: You want it?
MS. BURNETT: No. I’m good, I have mine. I have it on my computer, so I can view it.
DR. SHANK: Okay.
DR. MARKS: Thank you, Christina. I know when I went through this I was going back to the original reports,
which the last one I have is on page 226 of the PDF, which was the conclusion on the silicate aluminum magnesium,
et cetera. Okay.
As Christina documents in her memo on May 23rd, this is a re-review. And basically, we have a conglomeration of
stuff. There are ingredients -- there is the suggestion to consolidate ingredients from three reports previously. And
they are on page 89, 155 and 226, for those who want to refer to that. And then 16 add-ons.
And then, in terms of the reports themselves, in 2003, there are 17 silicates that were safe. Then in the next
paragraph, Christina talks about the 16 possible add-ons. And then, let me see, in the 2005 and 2009 reports with -I have to look at the conclusions. Did I put -- are they all safe? Or one them was irritation, wasn’t there?
MS. BURNETT: 2005 the potassium sodium, metasilicate and sodium silicate have a formulated to be
nonirritating.
DR. MARKS: Nonirritating, yes.
MS. BURNETT: They were part of the original group, that were reviewed, and the panel decided to split them off.
Then during the discussion in 2009, for the silica report, it was mentioned that when these were re-reviewed, thatthey would all be grouped together. I don’t know if you saw that; but I had a good laugh when I read that. Saying,
we will let the folks in 2018 deal with it. Well, guess what? You guys are all still here.
DR. HILL: Here we are. I saw that. I chuckled.

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MS. BURNETT: And you have to deal with it.
DR. HILL: It’s 2018 already.
MS. BURNETT: And just to remind the panel, the final report of the 2009 silica report was never published.
DR. MARKS: Yes. Thank you.
MS. BURNETT: It’s kind of hanging in limbo right now.
DR. MARKS: Yeah. Okay. Yeah, the irritation and sensitization were okay, except the silicates were irritating.
That’s page 83.
I think the first question, is do we want to open this? Obviously this 2003 report. And that can either be forchanging the conclusion, or it can be for add-ons and consolidation. Do we want to reopen or not?
DR. SHANK: I don’t think it’s useful to reopen.
DR. SLAGA: I’ve been with reopening this; I like combining all of these together.
DR. MARKS: Hmm, interesting.
DR. SLAGA: I don’t remember who pushed to have it separated a long time ago. I know the panel did, but I -MS. BURNETT: I don’t remember.
DR. SLAGA: The other group, way over there?
MS. BURNETT: The team minutes were not really published back then, so I can’t really tell.
DR. MARKS: Oh, is that right?
MS. BURNETT: It’s summarized.
DR. HILL: They’re summary versions.
MS. BURNETT: Yeah. They’re summary versions.
DR. SHANK: I don’t see how it’s useful, what that accomplishes. And I think you may have trouble publishingthat if most of the report is already -- if you put it all together, you’re going to have to justify it, to some journal, thatit’s already been published, now we’re putting it together. I don’t see -- it’s not worth the effort.
DR. SLAGA: Well, what about the 16 though? The 16 possible.
DR. MARKS: Yeah. That’s the question I would add, is the new 16 add-on ingredients that have never beenreviewed before.
DR. SHANK: Okay. There’s very little data on those 16, and only two of them are used. So that could be handled
in the re-review summary without reopening. I certainly would not combine -DR. SLAGA: Published data.
DR. SHANK: -- all of these into one report.
DR. ANSELL: That’s really our comment for recommending not reopening; is that we would like to hear a much
more substantive discussion as to why these three reports form a relevant family.
DR. HILL: Here’s what I wrote. I think in general, maybe we should bring everything together and get a global
view of properties; and then respectively separate into either different reports, or at least different subsections very
carefully constructed so any read across that is or isn’t used is very clear.
Sodium metasilicate is very different from synthetic amorphous silica or zeolite. And I’m also not prepared to readacross from sodium silicate to something like sodium aluminum silver silicate, or silver copper zeolite, where there
are different metals with different redox properties, blah, blah, blah, blah, blah. Anyway, so I guess I’m at a levelagreeing with Dr. Shank.
DR. SLAGA: But how do we deal -- there’s two of them that are being used.
DR. HILL: Which two are they?
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DR. SLAGA: Would that be worthwhile to add those two? I mean, being consistent with earlier, where we didn’t
want to add them because they were not in use. But two of them are in use out the 16.
MS. BURNETT: Ammonium silver and zinc.
DR. HILL: Ammonium silver -DR. SLAGA: I know doesn’t seem much to add but -MS. BURNETT: Ammonium silver zinc.
DR. SLAGA: -- some consistency here.
DR. ANSELL: Well, then we would just open up that report. We don’t have to open all three of them to merge
them. If we feel that -DR. SLAGA: No, no. Eliminate the others that have been published already. I’m talking 2 out of 16.
DR. HILL: Well then actually, the six that haven’t been published from 2009.
MS. FIUME: Right. So, it would be 22 that have not been published yet.
DR. SLAGA: Oh, okay.
DR. HILL: And are they across all three families?
MS. FIUME: The 2009 ingredients, that report has not been published. So, it wouldn’t be republishing existing
information.
DR. SLAGA: Which one?
MS. FIUME: The 2009 report. The silica and silicate ingredients. I mean, if there’s commonality to create afamily out of all of these -- or any of these; because we do need to consider, number one, the re-review. But once
you reopen the re-review, you don’t have to read across. You can make a split conclusion if the family fits together,but you don’t have enough information to decide on all of them.
You can do a split conclusion. It doesn’t have to be read across. Once you decide to reopen, you know, if you’re
combining -- because there are different conclusions among the ingredients you would be combining. Then you canstart a whole new review.
DR. ANSELL: I think we would have an issue with reopening to add an ingredient, and then determine that theexisting data is insufficient to support that new ingredient.
DR. SHANK: That’s not a no-brainer then.
DR. ANSELL: Yeah. It would need its own report, which you guys could always do.
DR. SHANK: Why were the six ingredients in 2009 never published?
MS. FIUME: I believe the journal may have liked to see some additional information, or it may have needed a little
bit of -MS. BURNETT: Reorganization.
MS. FIUME: -- reorganization for publication.
DR. SHANK: So, it was sent to a journal and the peer review said change it?
MS. FIUME: I’m not sure if it’s an internal decision or if it was a journal decision. I’m not sure, at that point, if it
was done or not.
DR. SHANK: Okay.
MS. BURNETT: It’s been almost ten years, so.
MS. FIUME: Yeah.
DR. ANSELL: Yeah. And I think that’s our core point. I mean, safety is one thing. We just don’t understand why
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MS. FIUME: Well, we have done it in the past, where we’ve reopened and based on the ingredients themselves,the conclusion it may not have been worthwhile to go forward. But we have created bigger families and looked at it
as a full report, not simply -- once the decision was made to reopen because some of them were no brainers, thosewere brought in, because we were initiating a full report.
So, we’ve done it both ways in the past. But again, it’s the panel’s purview as to how they’d like to go forward,
with this group, based on the similarity -- the information that’s already included.
DR. HILL: For me, the 2003 grouping is a strange looking family. I mean, I would have put the clays together andthat’s it. You know, and then some of these other silicates together and that’s it.
And then some of the new ones and some of these ones in the other report fit with that, but not that. You know, sothat’s when I say -- I mean, you published in 2003, you reached conclusions, but it’s a strange grouping.
DR. MARKS: We’re still at the point -- initially, we said we did not want to reopen. We don’t want to consolidate
the ingredients from the previous reports -- the previous three reports. Two out of the three reports were published.
And then we didn’t like all the add-ons, but two of them are being used. Do we reopen to address the two add-ons
that are being used?
And then obviously, the comments you made, Ron Hill, about the lack of consistency of the grouping of theingredients raises some issue. Although that 2003, all them were safe. Even though maybe the grouping isn’t toyour liking.
So, where should we go team? Do you want to not reopen, or do you want to -- and which of the two of the new
add-ons are being used?
DR. ANSELL: Ammonium silver zinc -DR. HILL: Aluminum silicate. It’s the fifth one down in her table. And zinc zeolites, all the way at the -DR. MARKS: Zinc zeolite. That’s one use. And then what was the other? The ammonium silver zinc aluminumsilicate, is that the one?
DR. HILL: Yes.
DR. MARKS: And how many ingredients is that? Or how many products?
DR. ANSELL: Seventeen.
MS. BURNETT: It’s in 17 and has a use concentration.
DR. MARKS: Yeah, 17 is a lot.
DR. HILL: So, one way to fly on this, or at least for discussion to think about, is pull ingredients out of that 2009group that never got published, that go with this one or that one. I don’t see any zeolites, but there are silicates thatwould fit.
So, you pull the silicates that go with the ammonium silver zinc aluminum silicate and see what data you got. And
then we had that sassy publication in the interim. I think that was actually my second meeting here in 2009, if I’m
not mistaken.
And we have the whole transcript covered, which I captured, which I read. And I thought that was -- it reminded meof things I heard -- it’s hard to say, nine years ago, but nine years ago.
DR. MARKS: So, what you’re suggesting is -- and that would be reopening, but not reopening the ’03 report,
reopening the ’09 report. Because it is a report even though it wasn’t published.
DR. HILL: Well, it never was published.
DR. MARKS: Well, that doesn’t matter. From a CIR point of view, it’s a report.
DR. SHANK: Right.
DR. MARKS: Am I not correct?
DR. SHANK: Yes.

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DR. HILL: I got you. Okay, well -- okay then maybe -DR. SLAGA: But that could be decided some other time.
DR. MARKS: We could talk about that today and perhaps -- so we don’t want to reopen the 2003 report? We’repretty solid about that.
And then should we mention, tomorrow, to consider -- because it’ll be very interesting to see, obviously, what theBelsito team, their approach. Our approach would be to reopen the 2009 report and add, where appropriate, the new
add-ons which is -DR. HILL: It’s really the one that has 17 uses, I think, I heard.
DR. MARKS: Seventeen uses. The zeolite is chemically significant, different from the silicate ingredients in the2009; you would include that, since that has one use?
DR. HILL: Yeah. I mean, if you’re going -- a re-review summary is going to be written for the 2003; so, if you
don’t want to reopen, I guess then that zinc zeolite stays in orphan. Is there any downsize to having it stay in orphan
other than just one we have in the dictionary that’s not been reviewed?
DR. MARKS: Right. And the other is if we suggest the 2009 report, 15 years, that’s 2000 -- let me see, 2024
right? We put it off for another eight years or so.
DR. SHANK: Beyond my time.
DR. MARKS: So, second, not reopen the 2003 report. We’re solid on that one, team? And then we could consider
reopening the -- our suggestion would be if there is -- it doesn’t sound like there’s any urgency to these new addons. I mean, is the aluminum silver -- there are no alerts or concerns about these two that are in use.
MS. FIUME: Not that I’m aware of. But I can I just -- for a procedural question. I know there’s been a lot of
discussion this morning about whether they’re in use or not in use. As part of the reopen decision, which is a newturn as I’m sure Dr. Bergfeld will point out tomorrow. But a lot of these silicates that are just a combination ofaluminum, or calcium, or magnesium, which were in the 2003 report, you don’t feel they can be no-brainers; andadded to that report and be reopened for add-ons as no-brainers?
DR. SLAGA: I mean, that’s what I originally thought.
MS. FIUME: That would be our typical -DR. ANSELL: Ammonium, silver, zinc and zinc zeolite add to the ‘03.
MS. FIUME: But there is aluminum calcium magnesium potassium sodium zinc silicate. And you know, we’ve
done aluminum silicate. And, you know, we’ve done aluminum silicate, we’ve done calcium silicate, we’ve done
magnesium silicate. So, there is a calcium magnesium silicate as a proposed add-on.
If you don’t want the entire list of 16 -- regardless of in use or not in use -- are there some that can be brought in as
no-brainers, and brought into the 2003 report? And would you consider, at least, taking that step?
DR. HILL: For me, as soon as you have silver in there then that’s not necessarily, chemically a no-brainer withoutsome additional information. Because there’s nothing with silver in it, on it, or around it, in the original 2003.
DR. MARKS: Okay.
DR. HILL: And that has redox properties that aren’t present in these other metals from the 2003 one.
MS. FIUME: But there is a calcium magnesium silicate.
DR. SLAGA: Right.
DR. HILL: Silver is nothing -MS. FIUME: There’s a sodium magnesium aluminum silicate, as ingredients that have not yet been reviewed.
MS. BURNETT: So, possibly eliminate the silver ones.
MS. FIUME: So, could they be brought in reopened to add these no-brainers?

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DR. MARKS: And then we can list the specific ones. But I see what you’re saying, that of the potential add-ons,
limit that 16 to ones which are chemically very similar to the 2003 report no-brainers, and reopen and add those.
Don’t consolidate.
Tom, you seem to be indicating that sounds okay. Ron Shank, do you have a problem with that? And we can list
which ones. We mentioned the calcium magnesium silicate, and there are several others -- or a couple others. Whatis your sense, Ron Shank?
DR. SHANK: You’re taking the no-brainers from the new add-ons?
DR. MARKS: Yes.
DR. SHANK: And adding them to the 2003?
DR. MARKS: So, like calcium magnesium silicate would be one of the no-brainers. Not silver, based on Ron
Hill’s concern.
DR. SHANK: Okay. So, out of those 16, the only -DR. MARKS: Yes. So, let’s go there.
DR. SHANK: -- one that is used is zinc zeolite.
DR. HILL: And ammonium silver -DR. SHANK: Or the silver. And Dr. Hill says count in -- that’s not a no-brainer. So, you’re reopening to add zinczeolite, which has one use.
DR. SLAGA: No, no. Add even the ones that are not being used -DR. MARKS: Calcium magnesium silicate.
DR. SLAGA: -- to this because they’ve never been reviewed.
MS. FIUME: I mean, they’re in the dictionary.
DR. SLAGA: We eliminated -- re-reviewed based on it wasn’t a no-brainer. That was the final earlier today.
These are -DR. ANSELL: So, you dropped silver. You’d keep germanium?
DR. HILL: There’s still quite a few that you could keep though.
DR. SHANK: What about iron?
DR. HILL: Yeah. I think so.
DR. MARKS: So, let’s go from the top. Obviously not activated clay. How about the second one, the aluminum
calcium magnesium potassium sodium zinc silicate?
DR. HILL: So why not activated clay, because you’ve already got -- in the 2003 -- you’ve got attapulgite,
bentonite, Fullers Earth, hectorite and kaolin.
DR. MARKS: So, you would add that?
DR. HILL: I think activated clay would be fine.
DR. MARKS: Okay.
DR. HILL: The next one would be fine. The next one would be fine. The next one would be fine. The next one
would be fine. Then we’ve got two silvers, but I think the calcium magnesium silicate would be fine.
DR. ANSELL: Calcium magnesium germanium would be okay?
DR. HILL: Where’s that?
DR. MARKS: Well, no.
DR. ANSELL: That’s number three.
MS. BURNETT: The third one down.

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DR. HILL: I don’t know about germanium. That’s iffy. I’d have to think about that. I’m sorry I didn’t yet.
Remember, my take was put them all together and then split them back out. But, I’m in a different mode now. I
think germanium would be okay.
DR. MARKS: Okay. So, you don’t like the silvers. Now we’re down to the gold zeolite. Zeolite was safe in the’03 report. Adding gold to it, does that change it? And then we’re into silver copper zeolite.
DR. HILL: So, I’d have to see what the definition of the gold one -- it really isn’t very clear if I remember right.
MS. BURNETT: Yeah.
DR. HILL: What form the gold is in.
MS. BURNETT: Gold zeolite is a product obtained by the reaction of gold chloride with zeolite.
DR. MARKS: Yeah. So, it’s gold plus zeolite.
DR. HILL: I have to think about that one and the germanium. But anyway, skipping that for the moment and thetwo silvers, then you still -- you have sodium magnesium, aluminum, here’s another silver. I think titanium’s okay.
Tromethamine is new. So I flagged that at least.
But then the last of them is probably fine, based on what’s in that grouping in 2003. I know it seems like I’m cherry
picking, but I’m just looking at chemistry that I know.
DR. MARKS: So, you would have two, four, six, eight, nine ingredients if I count -DR. HILL: Six, seven, eight, nine, maybe ten if we do zinc silicate. Did you catch that one?
DR. MARKS: Yup.
DR. HILL: Let’s see, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 I count.
MS. BURNETT: I have nine.
DR. MARKS: Oh, I didn’t include the gold since you were hesitating.
DR. HILL: No, I didn’t. but I did include the last four -- all of the last four.
DR. MARKS: Okay. The last four.
DR. HILL: But that’s just -MS. BURNETT: Eliminating all the ones with silver.
DR. HILL: And I’m not sure about gold; I have to think about that.
DR. MARKS: And you’ve eliminated the zinc, the one that has 17 uses, the ammonium silver zinc aluminumsilicate. So, we’re adding on virtually everything with no use; although that hasn’t been a -- these are no-brainers.
DR. HILL: And now the interesting question is, would you group all the ones that had silver and possibly with thegold in there, and then make another group and another report. But the only ingredient that’s in use -- and I don’tknow about data -MS. BURNETT: None of those are in use.
DR. HILL: -- would be the ammonium silver zinc aluminum silicate. What do we have in the way of data?
DR. MARKS: So, now we’re at reopen the 2000 report and add approximately -- I’ll say approximately -somewhere around ten ingredients, which are no-brainers from that new add-on list. What’s your sense, Ron Hill?
You don’t have a problem with that?
DR. HILL: I don’t have a problem with that; or I don’t have a problem with do not reopen, since most of those are
not in use.
DR. MARKS: Ron Shank, which way do you lean? Still not reopen.
DR. SHANK: Yes. Not reopen.
DR. SLAGA: Reopen.

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DR. MARKS: So, we have a split here. I mean the question is, is it really worth it for a bunch of ingredients thathave no uses. But that shouldn’t be -DR. SLAGA: Well, zinc zeolite a product, right?
DR. MARKS: Yeah. One use for that one.
MS. BURNETT: I have data on that one.
DR. MARKS: But again, that’s the criteria. Do we use that criteria for reopening? Some things I don’t think wehave. It’s just as a no brainer.
MS. FIUME: I would like to state CIR has been trying to create, through the past couple of years, complete
families, even if ingredients had been reviewed in the past.
DR. MARKS: Right.
MS. FIUME: Regardless of the number of uses. Because then I was going to channel Bart, a little bit, and say
thank you for potentially adding the add-ons to the report. But then can we look at the 2005 and 2009 reports,
because again, there are similar ingredients. So that our family is complete, in one place, could you consider
bringing those into the report as well.
And they do have conclusion, but again, there is sodium potassium aluminum silicate in the 2009 report. So, it’ssort of out there.
I guess one of our goals has been recently, as we prepare these bigger families, is that it makes sense to have afamily of ingredients in one place. And that’s, you know, what we’ve been striving to do. So, is it possible to make,even albeit large, a family of ingredients out of these combined four categories, if it was going to be redundant.
DR. ANSELL: Right.
DR. MARKS: And that’s -- Ron Shank, right from the beginning, you didn’t like the idea of combining all into one
report?
DR. SHANK: I didn’t see the need. Had that been done at the beginning, okay. But to go back and put them all
together, half of them have already been published. So, now what you’re saying is taking the 16 add-ons, and the2009, and putting them all into a reopened 2003.
DR. MARKS: No. Actually -DR. SHANK: And leaving the three irritating ones -DR. MARKS: No. I wasn’t that far along, Ron Shank.
DR. SLAGA: Ten out of 16 for the -DR. MARKS: I was leaving 2009 standalone. And what I thought we were at was just taking the no-brainers andadding it to the 2003, which was proposed.
DR. SLAGA: That’s all we’re doing.
DR. SHANK: But there are no-brainers in 2009.
MS. FIUME: My request -DR. MARKS: Well, that’s already been -DR. SLAGA: And that’s what creating a family is.
MS. FIUME: Yes. If you were going to go ahead and reopen it, then could we look at the 2009, 2005, and say yes
there are actually a lot of ingredients that also belong in that family, so that they’re all in one place; if it were to be
reopened.
DR. SLAGA: No-brainers.
DR. ANSELL: Right. But I think you’re turning it kind of upside down. The reopening justification now is toorder the family. And I think that was our original question, is that worth the effort?

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MS. FIUME: Well, I guess, step one would be, are there no brainers that are now listed that have not beenreviewed; and is that a reason to reopen to add. And if that is, we take that step. Then can we take the next step oflooking at ingredients that, yes, were reviewed, because we’ve done this many times, and bring them into the family
as well.
So, I’m looking at it as a step process; but if you go ahead and take the first step, is there any reason not to take thesecond step and create a whole family.
DR. SLAGA: Maybe that’s a way to bring it up, the way it was stated. That the 2003 additions, no-brainers, andthen approve that, and then say there’s a possibility that the others could be brought in for a family relationship.
MS. BURNETT: I would like to point out that some of the potential add-ons that have the iron included, the iron
was reviewed in 2009. You wouldn’t have that data from the 2003 report, if that would aide anything.
DR. HILL: What you’re saying is we’re not sure if iron is a no-brainer read across. And I’m sort of asserting inthese kinds of materials, it pretty well should be.
MS. BURNETT: Okay.
DR. MARKS: Well, our team should at least -- there’s two different issues. We’re still at -- and we have a split
decision among the panel as to whether we not reopen versus open 2003 report and add the ten “no brainers”. I say
10, it might be 9 or 11.
DR. HILL: It’s around there, somewhere in there.
DR. MARKS: Versus the idea of reopening and consolidate. I hear you, Monice. Right from the get-go we said
we didn’t like to consolidate. But we also hear the idea, well this is in the same family, it’d be nice to have it all on
one report.
Consolidate? Because we’re back to that again. And we shouldn’t -- I don’t think we should go into tomorrow
wavering that way, if we all feel don’t consolidate. And we maybe have a split concern that way. It’ll be interesting
to see -- the good thing for me is I’m seconding the motion.
DR. SLAGA: That’s right. If they say consolidate all of them, we’d say we agree.
MS. FIUME: And as a reminder, we’ve done it in the past where we have reopened, and then the next time you cancome back and then look at it again as an entire family, with more information and change it.
But I just wanted to lay out all the steps. And I understand if it’s not reopened, you know, that’s the panel’s
prerogative. But I just wanted to lay out the steps of how to look at the thought process.
DR. HILL: And what you just said last was what I was proposing, even if it wasn’t obvious by how I said it; is put
the information together and then decide. But it’s staff effort and I really appreciate that.
MS. BURNETT: Already started, so it’s fine.
DR. HILL: Well, I mean, the problem is if they put you on something else -DR. SLAGA: Alright Jim, you heard that. You could either punch them tomorrow or double punch them.
DR. MARKS: No. I think it would be since we’re split on it, as long as they’re not split, we’re going to probably
agree to whichever way they want to go.
DR. SLAGA: They’re probably playing in their sandbox, right?
DR. MARKS: I see the advantage -- and I have in here consider consolidating with the 2005/2009 report. But myfeeling is if their team -- from what you said Christina you’ve already started that, that consolidating them is notgoing to be a huge issue from your point of view. Staffing point of view.
MS. BURNETT: No.
DR. SHANK: Am I the outlier? This is a housekeeping issue as far as I’m concerned.
DR. MARKS: Yeah, exactly.
DR. SHANK: Not a science issue.
DR. MARKS: Yeah.

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DR. SHANK: So, if you want to put them together, the staff won’t throw rocks at us -MS. BURNETT: I would have thrown those rocks a long time ago at somebody else, so it’s good.
MS. FIUME: She would have thrown the rocks at Bart and I.
DR. HILL: I think in putting them together and looking at subgroupings in terms of what can be read across as -- I
don’t know that there’s such as a thing as a real no brainer but anyway -- that fit that criteria to a reasonable degree.
And looking at sub -- I think some things will emerge that if we don’t put them together, okay the sleeping dog will
lie and there’s probably no disaster to that too.
DR. MARKS: I’m going to second what I think’s going to be the proposal to open the 2003 report. Put the addons; ten of them are we think no brainers. I’ll ask you to talk about zinc tomorrow so just so, Ron Hill, you indicate-DR. HILL: The silver?
DR. MARKS: Oh, silver. I’m sorry. Sorry, got the wrong metal. Silver, Ron Hill.
DR. HILL: I didn’t bring my advance inorganic chemistry book with me to look at germanium and gold.
DR. MARKS: And then consolidate with the 2005 and 2009 reports and we’ll see where it goes. I want to get toscience now that we’re past the procedural issues. Irritation and sensitization should be fine. It formulates to be
nonirritating. That takes care of the silicates.
As I read it, there was some issues with respiratory in this. Is that true or not? And if it is, at least going forward, I
wanted to get a preview of the science of the respiratory issues and how that’s going to be address with these.
DR. SHANK: And where are you in all this 272 pages?
DR. MARKS: I put respiratory okay, use table 75. I guess there must have been a few things in here. I’m sorry,
Ron, I just highlighted respiratory and I didn’t put a page. I’m not sure where when I look through the report. Ron
Hill?
DR. SLAGA: I didn’t see anything.
DR. SHANK: We have four reports all in one.
DR. MARKS: Yeah, exactly. Let me see if I -DR. HILL: I was looking at transcripts a lot and starting into this, since I wasn’t around at the beginning.
DR. MARKS: Sorry, Ron. Maybe just put as an alert and as we go -- when it gets all consolidated. It seems to me
it came out -- nothing stood out to you respiratory wise, Ron Hill?
DR. SHANK: Correct.
DR. MARKS: I mean, Ron Shank. Good.
MS. BURNETT: The summarized discussion from the original report mentioned -DR. MARKS: Here it is. Page 89.
DR. SHANK: Page 89?
DR. MARKS: Page 89. This was the 2003 report. And if you look at the end of -- it says, “Panel considered thatany spray containing these solids should be formulated to minimize their inhalation. With this admonition to thecosmetic industry, the CIR panel conclude that these ingredients are safe.” So that must have been -- not in aconclusion, but in the discussion.
And then when you look at page 149, right above -- yeah. The conclusion doesn’t mention any admonition to thecosmetic industry, which is kind of interesting. I thought that’s pretty strong wording to not have in the conclusion.
And then, if you look right above the conclusion on page 149, not the note, but right before the note. The
concentration of ingredients is very low. That’s the respirable concentration. Even so, the panel considered that any
spray containing these solids should be formulated to minimize their inhalation.

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That could have been a conclusion. We do formulate to be nonirritating. Can you formulate to minimize
inhalation? Or is that the way it’s delivered?
DR. SLAGA: That might be coming up soon.
DR. MARKS: That’s where I’m sure I got the inhalation concern.
DR. HILL: Yeah. I was reading back in the transcripts, and the discussion of talc came up which continues toremain an almost ridiculously contentious issue. But it’s out there, heavily, in the consumer world, in discussion.
Discussion, I use one word.
Because it mentions talc is a hydrated, magnesium silicate. And it gives the chemical composition. This is in the149, right above the conclusion. Occurs in various forms and has unique crystalline structure. And talc is notincluded in this report. The significance there goes to the no-brainer contention with these add-ons.
DR. MARKS: Okay. I just wanted to, Ron, bring that up, and Ron and Tom, about I suspect at some point we’regoing to -- I have to address that again with it being reopened.
DR. SHANK: The respiratory issue?
DR. MARKS: Yeah. Or whether the inhalation boilerplate addresses it.
DR. SHANK: I think it does.
DR. MARKS: Yeah, okay. I think that’s fine. Okay, well, we’ll see what happens tomorrow. I’m planning on
seconding it -- whether it’s the motion or not -- opening the 2003 report with ten no-brainer add-ons. Silver, Ron
Hill, has concerns. And depending on what, I’ll ask you, Ron Hill, to -- and then we’ll consolidate with the 2005
and 2009 reports. Does that sound okay now to everybody?
DR. SHANK: Yes.
DR. MARKS: Good. Okay. And we’ve taken care of the respiratory. Okay. Thank you.
Christina and Monice, that was a -- I don’t know, every ingredient we’ve had there has been some good discussion
so far. Are we going to have one where it’s, yes, that’s fine. Let’s move on to the next one.
Full Panel Meeting – June 5, 2018
DR. BELSITO: This is a re-review coming up from 2003, and there are 16 possible add-ons that have not beenassessed by the panel. There were also silicates that have been reviewed and were published in 2005, mainly
potassium silicate, sodium metasilicate, and sodium silicate.
And these would be additional materials that could be incorporated, so bringing that total of 19 into this report. But
then there was also in 2009, assessment of silica and related cosmetics, and that safety assessment, it turns out, wasnever published for some reason, and would be due in another six years.
We felt that we could reopen this report; and also in addition to what was reviewed in 2003, include the 16 possible
add-ons that haven’t been looked at. And include the ones from 2005, the three there, as well as the ones in 2009,that were not published. So, essentially add all of the prior reports on the silicates together, add the new ones.
We need to take a look at this because usage has increased significantly for many of these. And we need a sense of
the concentration of use before we decided on the safety. So, we would like to reopen, combine all of them, and at
this point our real interest is what concentration they’re used at. We may not need additional data based on that.
DR. BERGFELD: So, you’re asking just to reopen and add?
DR. BELSITO: Reopen, add the 16, and combine the prior reports on silicates.
DR. BERGFELD: Okay. Dr. Marks?
DR. MARKS: We second that motion. I just want to clarify. So, you don’t want to move forward with either atentative report or an insufficient data announcement with the reopening.
DR. HELDRETH: Reopening would be a tentative report.

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DR. MARKS: Okay then, if it’s a tentative report we have to have a conclusion, correct? And I haven’t heard aconclusion.
DR. BELSITO: Well then, I would say that it’s insufficient for concentration of use of what we’re adding on.
DR. BERGFELD: Okay.
DR. EISENMANN: But we were never asked to do a concentration of use survey, yet, on some of the ingredients;
so, it’s hard to make it to be a tentative report.
DR. HELDRETH: Yeah, we can put up the insufficiency, and we could give industry time to respond with that
information.
DR. MARKS: So, then it would be an insufficient data announcement.
DR. BERGFELD: Is that okay? Agreeable?
DR. BELSITO: I’m fine with whatever the procedures are. I think this will clear pretty quickly once Carol gets us
the data on concentration of use. But it’s hard to say “safe as used,” when we don’t know how the new ones areused yet.
DR. HELDRETH: Alternatively, we can concede that this can just be considered a report strategy, at this point.
And if you agree with the strategy, then we will create a new report that comes back to you.
DR. BELSITO: I’m fine with that.
DR. BERGFELD: So, it’s just a reopen.
DR. MARKS: And then you wanted to include, of the add-ons, Ron Hill had a question with the silver. You
weren’t happy with including that as a no-brainer on the add-ons?
DR. HILL: I didn’t do it as a no-brainer, but if we’re reopening, which we weren’t clear we were doing in our
session, fully reopening.
DR. MARKS: Oh yeah, we’re reopening.
DR. HILL: Okay. I didn’t know where we landed at the end. Okay, then I think we leave it in for now. But it’s
not necessarily a no-brainer, it’s not clear that we will, for sure, be able to read across, but leave it in for the
moment.
DR. BERGFELD: Any other comments? I’ll call to question then? All those in favor of reopening, pleaseindicate by raising your hand. Thank you. Unanimous.

DECEMBER 2018 PANEL MEETING – DRAFT AMENDED REPORT/IDA
Belsito’s Team Meeting – December 3, 2018
DR. BELSITO: Okay. Silica and silicates. This is the first time we're looking at this one too.
MS. BURNETT: Apologies, I'm going to hand out a last-minute submission from Women's Voices of the Earth.
DR. HELDRETH: Yeah, this one came out -- this submission came in really late, even after we put out Wave 3 toyou. Since this report is only in the draft stage, feel free to wait to really go into the details of this most recent
submission until the next iteration. We'll include this submission as part of the next package.
DR. BELSITO: Okay. One of the ingredients, before we even go to that, just looking at what we had, iszirconium. And it says the EU has prohibited zirconium, and zirconium silicate and its compounds, in cosmetic
products. And it's not even reported as being used. Should we just delete it from the things that we're reviewing?
Or should we include it, but we have no data on it.
DR. BERGFELD: Why did they do that? They're in lots of things.

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DR. BERGFELD: Zirconium?
DR. BELSITO: Zirconium. If you look at the cosmetic use, there are no reported uses for the zirconium.
DR. HELDRETH: So you could be insufficient for that one if the other ones are not a concern.
DR. BELSITO: I don't know why zirconium was a concern.
MS. BURNETT: The zirconium, that's in the report, was in the original review. It was in the original review of thesilicates.
DR. LIEBLER: I'm not sure I see why it doesn't belong. I mean, chemically -- I mean, you got zinc silicate. You
just incorporate the zirconium ions instead of zinc.
DR. BELSITO: And then NICNAS has recommendations for risk management for safe use, for human health or
the environment, attapulgite, potassium silicate, sodium silicate, and sodium metasilicate, that I also didn't
understand.
MS. BURNETT: So how they do -- if I understand, how they do their risk assessment approach, if it's a tier one -meaning they don't consider it be a risk to human health or environment, they don't pursue a next-step risk
assessment, which delves further into systemic -- they don't produce a health report. So, when you go into their
database, you print an ingredient, it will spit out whether it's a tier one, tier two. If it's a tier two, you usually have areport attached to it that has data.
DR. BELSITO: Okay. So Women's Voices of the Earth. Point one, physical and chemical properties.
Morphasilica are composed of very fine particles, 20 microns which aggregate loosely in the air. Again, criticize
that we're using an outdated report from 1961.
We had testimony in 2009, that when they're produced, they're 100 micros. And some applications they're milled
down to 10 to 20 microns. Websites for cosmetic grade silica commonly advertise their product as having medium
particle size of five microns.
DR. SNYDER: So, these are all microspheres?
DR. BELSITO: Yeah, but we state that they're fine particles which tend to aggregate in air. So, don't we alreadycover that claim? I mean, again, it's not particle size, it's what's coming out of the cosmetic, right?
DR. LIEBLER: I think this is one where it's probably worthwhile for Christina to go through these examples citedin Ms. Scranton's letter, and run them down their links provided at least. And to see how these relate to cosmetic
ingredients that are used, in industry. And if we need to revise our particle size discussion, we can do that next time
we meet.
DR. BELSITO: I mean, all the criticisms have to do with, material as supplied can have a particle size of less thanten microns, but not the material as used in a cosmetic product. So, if you look at each criticism, that's what it is.
DR. LIEBLER: Yeah, there's two issues in this letter: one is the particle size stuff, that goes the first page and ahalf. And the second is whether or not crystalline silica is present in cosmetic products. She points to data recordedwith the California Safe Cosmetics Program that appears to contradict the assertion, in our report, that only
amorphous silica is used. So, that also needs to be chased out.
MS. BURNETT: I did a little searching this morning; I went to the two links that they gave us. The one that is theCalifornia database, they have -- when you just put in silica, it comes back with both amorphous and crystalline as
one ingredient. It doesn't differentiate the two.

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MS. KOWCZ: Could that be the reason why they're reporting it?
MS. BURNETT: I think they're lumping it all together in California.
DR. SNYDER: We went through this before with the fumed silica versus the silica fume; one is crystalline andone's not, right? We talked about that previously.
DR. LIEBLER: So we need to -- we need to make sure that -- if this is a categorization error by lumping all silicas
together, in that database, that that could be established.
MS. BURNETT: I'm not sure how to flush that out, but we'll figure -MS. KOWCZ: I think we need to look into that, because I think if it is lumped together, then the companies thatare reporting silica are just reporting silica, because they need to -- they will not take the chance of not reporting it.
MS. BURNETT: From what I can see, there's no way to designate it as one or the other, it's just one. They went
ahead and categorized a thousand products with silica in it.
DR. LIEBLER: It should be possible to determine that.
MS. BURNETT: Determine?
DR. LIEBLER: It should be possible to determine whether either the entry field, for entries for those ingredients,
are limited to just silica; and it includes both, and so it gets tagged both ways, automatically, upon entry, or whether
or not it's just lazy reporting by the companies.
DR. KLAASSEN: Plus there are three or four other websites that she quotes here. We need to look at all of those
closely. We were given the impression that what really is used in cosmetics is ten microns and larger. That when
they did these studies, like in animals, they even "ground" them down to be five microns. We need to know,
absolutely for sure, what's going on here. What is the size? There's a world of difference between five and ten.
DR. EISENMANN: But even if the size is five, as you put it in -- as you put it with other things -- as you put into
product, final product, the particle size of the final product is what matters.
DR. KLAASSEN: In that case, we need data.
DR. LIEBLER: And that's true, but yeah, I mean, it's true and it's very reasonable to say that. But, if we don't haveany data to really support that, that if you put in, let's say, ten micron distribution, plus or minus five, into a productand then you measure the particles that result in the final formulation, then it's like 50 and up.
It would be great to have data to support that. It's certainly reasonable to assume that that could happen. But in theabsence of any data we can hang our hats on, it would come across as wishful thinking.
DR. SNYDER: I had a logistics question. Why didn't those come up in your search? Those ones that she found.
MS. BURNETT: They're manufacturer websites. I don't necessarily -- I have -- I'm still reorganizing a report fromits original format, and I do have some outdated data sheets. But when I went to go verify that those were still good,they were no longer -- the links were no good. The thing is, is that they label -- their product manufacturers give aname to their products, so it's harder to search for them. So, it's a general Google search that you have to come up
with in order to get a silica manufacturer, and it's kind of cumbersome.
DR. SNYDER: Okay. Thank you.
DR. LIEBLER: Does your search include that California Prop 65 database?

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MS. BURNETT: No.
DR. LIEBLER: Okay.
MS. BURNETT: Should it?
DR. LIEBLER: I don't know. I guess that's a question I'm asking.
MS. KOWCZ: That's where she's getting the information.
MS. BURNETT: Yes.
DR. LIEBLER: Okay.
DR. HELDRETH: I think we'll have to determine if that's a credible source even.
DR. LIEBLER: Well, you know, it would be good to establish that. Because if that's a site that's being used -- you
know, that would be mined and generate data that's going to contradict us over and over again, I mean, it's anunforced error not to look. So, we should be looking at that and evaluate the reliability so we can determine how todeal with this, because it will be coming up again in the future, I suspect.
MR. GREMILLION: That's a California government site. It should be fairly credible you'd think.
MS. KOWCZ: Yeah, but also, she mentions that some of the websites, of the cosmetic suppliers, are saying that's
crystalline silica and it needs to require warning language. I don't think, normally, a supplier would tell amanufacturer what they need to say or not say. So, that's a question as well.
DR. HELDRETH: So, we'll include those in the response document that you see in the next panel table iteration ofthis report.
DR. BELSITO: When I looked at this, I was ready to go safe as used when formulated to be non-irritating, anddiscuss, extensively, the respiratory issues. But are we now saying that we're insufficient for information on the
respiratory issues?
DR. BERGFELD: Particle size plus. Don't you have to have --?
DR. BELSITO: Well, that's the respiratory issues. Is it inhalable?
DR. BERGFELD: Okay.
DR. KLAASSEN: I agree.
DR. BELSITO: So, insufficient for understanding of particle size and formulation, which we're not going to get.
DR. EISENMANN: But in other products, is it safe when formulated to be non -- so you're concerned about sprayand some powder -- and loose powder products?
DR. BELSITO: Yeah, we could say safe when formulated -DR. EISENMANN: For like in toothpaste. I mean there's a lot -- like silica. That's a big use for si- for like sodium
silicate, and sodium metasilicate were used in like hair bleaching products. It would be nice to have theinsufficiency carved out, more specifically, so that the other uses are safe, or put safe when formulated to be nonirritating, if that's where you're headed.

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DR. BELSITO: I mean, the real issue is, yeah, we know they can be supplied at less than ten microns. The
question is, is what happens when they're put into formulation? Isn't it really a more stringent conclusion -- we're
not going to get data from every single formulator for aerosol products as to what the particle diameter size is.
We've been doing this for -- safe when formulated to be non-irritating, safe when formulated to be non-sensitizing,safe when formulated in aerosol products so that the final aerodynamic diameter is whatever.
DR. LIEBLER: Is non-respirable.
DR. BELSITO: Is non-respirable.
DR. LIEBLER: Yeah, we never use that, but I was just thinking the same thing. We either do that in the
conclusion or we heavily emphasize it.
DR. BELSITO: No, we put it in the conclusion, because we're never going to get the data on all the products thatare respirable.
DR. LIEBLER: I'm okay with that. We could have a new -- this might be something that we might need to utilize
more often than a boilerplate, for aerosols. When we know we're not going to get the data; when we can't reallyarrive at a definition of safety. And so much of it will hinge on how the product comes out of the bottle's nozzle
whatever, in the final formulated product. And that's really all up to the manufacturer.
DR. BELSITO: So, I mean, safe as used when formulated to be non-irritating and non-respirable.
MR. GREMILLION: What does non-respirable mean?
DR. BELSITO: Less than ten microns.
DR. LIEBLER: The particles can't get down into the lungs.
MR. GREMILLION: No, I understand-, but where would you draw the line on that? My understanding is that a
lot of these products have at least one percent, or whatever, that's less than ten microns. Would you define that?
DR. LIEBLER: If we took this approach, we would need to probably put that into our boilerplate document that
we're currently working on. And then also, probably, have that in the discussion, drawn from the boilerplate
document, that would explain the relationships between particle size and respirability. And then the thing left for us
to determine, is do we want to put some kind of a threshold on that?
MR. GREMILLION: It seems different than formulated to be non-irritating, where that seems like something
that's either irritating or it's not irritating; whereas, respirable, everything's going to be a little bit respirable.
DR. LIEBLER: One of those endpoints are analogic.
MR. GREMILLION: Okay.
DR. HELDRETH: So, just to be clear, if it were small enough where we believe it will enter the lung, are we
considering whether or not there would be some sort of systemic absorption; or are we talking about irritation or
sensitization to the lung?
DR. LIEBLER: So, in the case of silica, that appears to be the issue.
DR. HELDRETH: Irritation or sensitization of the lung?
DR. LIEBLER: Oh, I'm sorry.

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DR. SNYDER: Deposition into the lungs.
DR. LIEBLER: Deposition, and lung and toxicity, the results for that.
DR. SNYDER: They have a lot of data. But some of it we don't know the particle size. Or some we have particle
size, some we don't. But there's clearly an effect.
DR. HELDRETH: Okay, I just want to be clear on that. Because for silica ciliate, we previously concluded safe
when formulated, and delivered in final product not to be irritating or sensitizing to the respiratory tract. But, if
we're talking about systemic absorption, that's a different thing.
DR. SNYDER: That's what we discussed when we talked about aerosols. There's a big difference between
experimental conditions and consumer conditions of use.
DR. BELSITO: So, what are we saying tomorrow? Non-irritating, non-respirable, and we need to define nonrespirable in our boilerplate?
DR. SNYDER: Correct.
DR. LIEBLER: Yes, I agree.
DR. BELSITO: Okay.
DR. SNYDER: Dr. Marks is presenting.
DR. BELSITO: All right. Good.
DR. SNYDER: We're off the hook.
DR. BELSITO: Okay. Well no, we're not off the hook.
DR. KLAASSEN: Sort of.
DR. BELSITO: Okay. We are done, unless there's anything else.
DR. BERGFELD: So, if you can't modify your boilerplate, or you can't address the inhalation -- if we can't modify
your boilerplate, or you can't rectify your use and formulation, what will you do, go unsafe for that -- safe sprays orinhalation?
DR. BELSITO: Unsafe for inhalation. But I don't think we're going to need do that. We'll see.
DR. SNYDER: Insufficient.
DR. BELSITO: Insufficient, yeah.
Marks’ Team Meeting – December 3, 2018
DR. MARKS: And let’s see. The next ingredients are silica and silicates.
MS. BURNETT: Are you ready for another Wave? We had a late comment submission from Women's Voices of
the Earth.

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DR. SHANK: We need to have control over -- we love to have data and information, but we need time to consider
it.
DR. HELDRETH: I agree. And I wanted to add the comment of, since this is not a final report, we can add this aspart of the next iteration to that report package; and you can take time to consider these comments, in detail then, if
you choose.
DR. SHANK: Okay. I like that.
DR. HELDRETH: We just wanted to -- since it came in, we wanted to provide it and make sure you have it.
DR. ANSELL: And we would appreciate time to read it, too.
MS. BURNETT: We did consider holding it, but one of the points that was made by them, I thought was a little -that needed attention, potentially going into either a comment period or into an IDA period, where we could researchmore. But that’s -- otherwise -DR. ANSELL: Which particular one was that?
MS. BURNETT: The comment about the crystalline silica.
DR. HILL: Yeah, my concern, in general, related to what you all just said, was that we’re calling this an amended
report, but we’re adding in a whole mess of new ingredients. And we aren’t capturing, in this report, all of theinformation from previous ingredients in the other reports.
We’re saying, here’s this report. And then, if you go through the report and you look, you see information. Really,
it’s all silica, or -- I mean, a very restrictive set there. And we’re adding in how many new ingred- -- 23, isn’t it, orsome large number of -MS. BURNETT: Well, original report was the 17 silicate ingredients; and then, the panel chose to reopen to add in
the three from another report, and then the nine from the silica report. Nine or Seven -- nine. And then a few justnew ones that haven’t been reviewed.
DR. MARKS: Well, 15. So, there are 23 additional ingredients added. Nine that were previously reviewed by thepanel, 15 that have not been reviewed, so that’s the 23. So, it’s 17 from the original report in ’03, to adding some
ingredients that had previously reviewed, plus the ones that have not been reviewed.
MS. BURNETT: There was 15 that -DR. MARKS: So, the total of 40 ingredients.
DR. HILL: And then, chemically, there’s a lot of diversity in those ingredients. As I was going through it, I’m
saying, this doesn’t feel like an amended report anymore, it feels like a new report. And that’s fine, but it -DR. MARKS: At this point, we have in front of us, a draft-amended safety assessment of silica and silicate
ingredients, containing the 40 ingredients we just talked about.
We’re at the point, do we go ahead and move forward with a conclusion of the tentative amended report, safe when
formulated to be non-irritating; or do we issue an insufficient data announcement? And obviously, we’ll be able toaddress the Women's Voices for the Earth at the next review of this, if we want, unless you want to take a few
minutes and look over the letter.
MS. BURNETT: While we were discussing the earlier ingredients, I did go and look at the -- for the crystalline
silica comment that they made, saying that they did research and they see that it’s being used in cosmetics --Distributed for Comment Only -- Do Not Cite or Quote

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DR. ANSELL: On 484, yeah.
MS. BURNETT: -- I did go to the two websites that they proposed. And the one, when you just put in silica, it
comes back as only one ingredient matched, and then it goes, then, to say that they’re synonyms. Crystalline is thesame as amorphous, is the same silicon dioxide.
DR. ANSELL: There are many errors in the 484 database. For example, no one’s actually using cadmium as aningredient. Ethylene oxide is not an ingredient. People have -- and there’s no mechanism in which to correct thefilings. So, whereas I find their database quite user-friendly, the quality of the data is somewhat questionable.
MS. BURNETT: And it’s also -- when you click on the word silica, silicon dioxide, amorphous silica,
microcrystalline, it then talks about how it’s manufactured from quartz and crystal (inaudible). But according to thedata we have, these silicas that are used in cosmetics that are synthetically derived.
I think the CAS number is generic and it applies to both the crystalline and the amorphous type. I think I rememberthat somewhere in the report.
DR. ANSELL: No, no. Obviously, I’ve not had a chance to look at -MS. BURNETT: Oh. So, I don’t know if that’s causing their error in their database.
DR. ANSELL: Well, no. I -- yeah. I mean, I’ve not had an opportunity to look at this. But we’ve looked at the
California Safe Cosmetics database, quite extensively, and it has some useful information. For example, many
cosmetics are white. Close to 90 percent of the filings are for titanium dioxide. But it also contains materials whichshould not have been reported, because they’re obviously not being -- well, they best not be being used as cosmetic
ingredients, heavy metals.
There’s no assessment, on California’s part, as to the accuracy of the any of the filings. So, we find it an interesting
database, but I don’t know that it’s interpretive to this extent. Even the listing of materials, California points out, arelisted because of data which may not be relevant to cosmetics, may contain ingredients which are not used incosmetics, or used in cosmetics, and not present a risk, because they do not do any type of risk assessment. So, it
doesn’t surprise me that silica might fall well within that context on the stake or -MS. BURNETT: Okay. I was just -- that was the main thing I was concerned about, coming out of coming out of
the memo. I know, with the micron size, we were reworking the aerosol. And I didn’t feel that that was an
immediate need for attention by the panel. The crystalline definitely was going forward.
DR. ANSELL: But we should definitely read the letter, and prepare a thoughtful response; and hope that their
response to our response is as thoughtful.
DR. HILL: So, just a general -- again, in looking at this and saying, how is this an amended report? There arequite a few substances in here. I should be able to go ingredient by ingredient if I’m going to conclude safe at somepoint, and say, what is this stuff?
And that got me to thinking, somebody is selling this ingredient to formulators who are formulating it. There will
generally be a lot of information in their information sheets, whatever they’re using for their marketing materials,
about, what is this stuff? How does it behave? And I don’t feel like, sometimes, we get that information. And I
don’t know why we don’t get that information, really, from anybody who’s vending -- I mean, principle.
But at least, I should be able to answer the question, substance by substance by substance, what is this stuff? I see aname. But in general, when it’s sold, what is the particle size? In general, when it’s sold, what’s the chemical
stability? In general, if you put it on mucus membranes, how will it react chemically?

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All those information relate to and -- is a phagocytose. So, if macrophages are swallowing the stuff, where does it
go? Do we build it up in lymph nodes? All those sorts of things. But the least fundamental question is, chemically,
what is this stuff? And I don’t get that, other than just, okay, it’s got calcium and iron and zirconium. Probably not-- Zirconium is talked about in there, but anyway.
So, in terms of data needs, I need enough information in each ingredient if I’m being asked to read across. Because
they’re clearly not all silica. Silica is just silicon and oxygen and nothing else. But we do have some zeolites andclays, and so forth in there, so that does potentially allow read-across if you have more information.
DR. MARKS: Ron Shank?
DR. HILL: And again, how to capture it. Because it is -- that’s the situation. What I put is, we have a lot of x’s in
the boxes, on the profile page, that are not captured in this particular report in any way whatsoever. It’s, go out andread that report, and that report, and that report, and that report. And I’m not sure we should put together a reportthat way.
I mean, I realize we don’t put the whole substance of the previous reports in there, but there should, some way, bedata that’s captured either tabulated or something, so that we can look at this report. A reader can look at this reportand make conclusions about read-across, if that’s what we’re being asked to do, which we are. So, there are at leastsummaries of other ingredients in this report, so that I’m not just looking at silica, silica, silica, silica, silica. But
that's me.
DR. MARKS: Tom?
DR. SLAGA: I didn’t have any concerns related to the ingredients, but to me they are the type of ingredients that
we had reviewed in the past. And as you said, this is a reorganized -- most of them are safe already that we havestudied. And we’re only dealing with 18, I felt, that were not reviewed, and that there was sufficient read across for
those; not every one, but enough data to support that these are safe.
DR. MARKS: Ron Shank?
DR. SHANK: I kept the whole group together.
DR. HILL: I concur.
DR. SHANK: I thought there was very little sensitization data and we need more.
DR. MARKS: Interesting.
DR. SHANK: And some of the use concentrations are very high. 80, 100 percent, et cetera.
DR. MARKS: Yeah. Kaolin at 53 percent, silica at 82 percent. I also had very little sensitization data. But then,when I go back and look at, there are just no alerts, and silica is not a sensitizer. And those had been reviewed
before.
So, I kind of felt we could go ahead as one of the conclusions in past, safe when formulated to be non-irritating.
There was some concern about irritation. So, I felt sensitization would be okay in this case, even though it’s not at ahigh concentration. But we do have sensitization data at, like, 50 percent on them, even though 83 is not 50 percent.
But a local lymph node assay -DR. SHANK: So it’s not like palmitic acid -- palmitate?
DR. ANSELL: No. It’s more like sand.

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DR. SHANK: No, I’m just saying, the sensitization -- last ingredient, we had it -DR. MARKS: Yeah, I know. I agree. That’s it.
DR. SHANK: We had it at one level, but not a little bit higher. Now it’s okay, because it’s sand?
DR. MARKS: Yes. Essentially, yes.
DR. HILL: I need to qualify my earlier remarks by saying, I don’t have any serious toxicological concerns withany of these, even by name only.
DR. SLAGA: It’s just enough -- enough on each ingredient.
DR. HILL: But I still have the fundamental thing that if I can’t answer the question, what really is this stuff, how
do I read across to it and clear it? And I don’t know why, if somebody’s selling this, we don’t have information as
to what is this stuff, in every single instance that it is being reported to being use. And if it’s not reported to beinguse, why do we clear it for safety as sufficient? We leave it insufficient until somebody comes forward with theinformation we need to answer the question, what is this stuff?
So it’s kind of a due diligence question for me. I wrote, for example, what do we know about the thermal stability?
I was even curious -- from the other end, they, apparently, have excluded the ones that have zirconium in them inEurope, I believe. And I looked and said, well, why? That zirconium’s not coming out, so what’s the problem? I
often rail against pseudoscience because I abhor pseudoscience.
DR. MARKS: It’s interesting, Ron, I had that initially. And then when I went back and reviewed, I felt the same.
This is sand, even though it’s not at the concentration use, I clinically didn’t feel that it would be an issue.
DR. SHANK: That’s fine.
DR. MARKS: Yeah. And my main, when I looked over at -- besides what you were talking about, Ron Hill -- isare we happy with the inhalation concerns that have been raised? Is there any issue?
DR. SHANK: There are a lot of studies, but most of those studies were designed to get into the deep lung. The
particle sizes aren’t given, but they did have alveolar effects. So, they’re interesting from an inhalation toxicology
point of view; but I don’t think they relate to cosmetic use, because the exposure would be much, much different.
DR. ANSELL: We also have to be careful. They’re looking at lung defects, but they’re not truly inhalation studies.
Most of them, to get these doses, were instilled.
DR. SHANK: Right.
DR. ANSELL: So, it’s not really an inhalation exposure, per se.
DR. SHANK: Well, yes. The toxicologist put instillation in inhalation because, that way, they know they get it inthere by ramming it down.
DR. ANSELL: Right. Yeah.
DR. HILL: But it’s well to be thinking about that appropriately, because silicosis is a very real thing. And forsomebody who was using fumed silica multiple times, on an almost daily basis, all the time, and be real careful how
we handle it and tell the grad students how to handle it, we have to make sure that we -DR. ANSELL: Right. It’s relevant to hard rock miners.

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DR. HILL: It’s relevant to chemists working in labs, filling columns with silica all the time, every day, which, as I
said, I was doing. So, 10 micrometer, 20 micrometer, all the time, with fines in there that are very -- go up into the
air and that you don’t breathe.
DR. MARKS: So, I think, for me, that needs to be explicit in the discussion, that the inhalation concerns are not
relevant to the cosmetic use. Okay. I’m gonna go ahead, tomorrow, and move that a tentative amended report ofthese 40 ingredients, 17 previously reviewed and the 23 add-ons, are safe when formulated to be non-irritating. And
we’ll see if the Don’s team has any concern about sensitization.
Point well taken, Ron Shank. It’s a -- yeah. What can I say? I'm leaning, in that previous one, to say the clinicalexperience. Okay. And then, Ron Hill, you’ll have comments. Okay. Let me go ahead and close this. Save it.
DR. SHANK: So what’s gonna happen with this new -DR. MARKS: Oh, we’re going to -- oh, thank you. I should -- we’re going to address that at the next -- at least ourteam is going to address it at the next meeting, unless you all want to take a few minutes and read it. But I think
Christina or Bart are going to have to draft a response, just like Jinqiu has for another letter that we did get.
DR. SHANK: We could just respond that the panel will consider -DR. MARKS: Yeah. But I think we have to go, as we’ve done in the past, point by point. And we’ll look at thatthe next time. This is not the last time we see these ingredients.
DR. HILL: Right. So, in clarification, is this a draft tentative amended report? It just says draft amended report.
DR. MARKS: Just what I said, tentative amended report; which means it’ll go on to the next edition, will be thefinal.
MS. BURNETT: We treated it as if it was a draft report. So, what it comes out of today would be -- if you feel thatit’s safe as used or -DR. MARKS: Yeah. That’s what I -- safe when formulated.
MS. BURNETT: It will be issued as a tentative amended report.
DR. HILL: So, the next iteration would be, essentially, a final amended report.
DR. HELDRETH: Next time you see it, it'll be a draft of the final.
MS. BURNETT: It’ll be a draft.
DR. HILL: But if there was insufficiencies, it’d be a minimum of two more rounds?
DR. ANSELL: If there are insufficiencies, in a review, I would argue that the material should be removed. This is
not a first iteration. So, if we’ve added materials, in which the data doesn’t support them, then my answer would bethat they shouldn’t be in this report. Not that we need to find new data or materials.
DR. HILL: And that’s why I asked the question, because how do I know today, when I can’t answer the question,
what is this stuff, for 15 ingredients that are in here? That’s the point.
DR. HELDRETH: Yeah. If we do the assessment and we find that information is lacking, then certainly theassessment is already occurring and we should conclude that there’s insufficiencies there.

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It’s at the discretion of the panel, that any specific ingredient, the review of which may otherwise be deferred, forwhatever reason, shall nonetheless be included, at the discretion of the panel when other chemically related, orotherwise conveniently grouped ingredients, are considered. That’s the way our procedures read.
DR. HILL: Read it again, one more time.
DR. HELDRETH: Any specific ingredient, the review of which may otherwise be deferred, should nonetheless be
included at the discretion of the expert panel, when other chemically-related, or otherwise conveniently-grouped
ingredients, are considered.
DR. HILL: But does that apply to amending reports? Or is that first -DR. HELDRETH: That applies to any decision the panel wants to make. Basically, at its discretion.
DR. ANSELL: Yeah. But we can’t move it to a final stage, because it’s an amended, and then have materials,
which there’s a material deficiencies -DR. HELDRETH: This is a draft report. It would go out as tentative if they give a conclusion. If there’s
insufficiencies, this would go out as an IDA.
DR. HILL: Okay.
DR. MARKS: Well, I’m gonna propose -- move that we send it out as a tentative amended report, not as an
insufficient data notice. Good?
DR. SHANK: Okay.
DR. MARKS: Yeah. And then, Ron Hill, you can -DR. HILL: I object.
DR. MARKS: Yeah. You can.
DR. HILL: But I don’t think I’ll be the majority opinion. I’m just -- I object.
DR. MARKS: Well, we’ll find out. Let me go ahead and save this.
Full Panel Meeting – December 4, 2018
DR. MARKS: So, at the June meeting this year, we reopened a report from 2003, in which the conclusion of 17
silicate and clay ingredients were found to be safe. This amended report now would have 40 ingredients: the 17 that
I mentioned we previously reviewed and 23 add-ons, of which 9 of those had already been reviewed. Our team felt
we could move forward with a tentative amended report with a conclusion, safe when formulated to be nonirritating.
DR. BERGFELD: Is there a second?
DR. BELSITO: Trying to get to my -DR. BERGFELD: Okay. We’ll wait for you.
DR. BELSITO: We had some issues with respiration. And we thought safe as used when formulated to be nonirritating and non-respirable, with an extensive discussion of respiratory issues. I'll turn that reason over to Paul andCurt.

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DR. BERGFELD: Paul?
DR. SNYDER: I don't recall the non-respirable component yesterday.
DR. KLAASSEN: The non-respirable really boils down to what is the size of the particles that do enter the
respiratory tract. At one time, we were under the impression that they were all at least ten microns in size. But now
there appears to be some information that there might five microns, at least when it leaves the nozzle.
Then the question is, do they agglomerate in the air on the way to the lung and become larger? It really is a problemof having knowledge about what is the size that we're really talking about here. It's not clear to me what it is. I
think we need more information. Maybe the other team has a better handle on that than I do.
DR. LIEBLER: I think I might have been the one who floated the formulated to be non-respirable construct here.
This reminds me, in a lot of ways, of the sensitization situation; where we have, for example, botanicals that weknow contained a sensitizing ingredient, but may or may not be sensitizing, depending on whatever else is in the
product formulation and perhaps some other conditions.
We can't really know that in all cases. We can point it out, but we want to put in the conclusion somehow, so we say
formulated to be non-sensitizing. It's not that we're punting on the issue, but we realize that we don't have the data
to anticipate what would be the circumstances with all of the individual products and their uses.
I think a similar situation applies to particles and inhalation. We're going to talk about the inhalation aerosol
precedence in a few minutes. But it occurred to me that we're in a similar situation with the aerosols and particles;
where we know that there's evidence that the distributions could include respirable particles.
What actually happens, in the product, as Curt just said, depends a whole lot on what else is in the can, or in the jar,and so forth. That's not going to be known by us, and we can't simply say it's safe or unsafe. It might be, and it
might not be, it depends on the circumstances. So this seems to set up a circumstance where we might embrace a
new construct, where we say formulated to be non-respirable.
It's not intended to punt on the issue; it actually highlights the issue. It essentially says to the industry, you're thepeople who put the silica, in this case, into your product, and you need to be aware that you could produce -- you areprobably very particular about the specifications of the silica, that you order from suppliers to put into your product;but you probably need to be aware of what the particle size, and the potential for respiration of these particles, will
be in your product. That's the logic behind this idea, formulated to be non-respirable. I guess, I'd better quit
repeating myself.
DR. BERGFELD: Tom.
MR. GREMILLION: It's not clear to me what would be meant by formulated to be non-respirable. Would thatmean like an absolute prohibition on particles less than ten microns?
DR. LIEBLER: That's impossible. Because these distributions always contain a tail that include the small number.
This is something that perhaps we need to talk about more, what that might be in practice; maybe that goes into theprecedence document. Is there a percentage less than ten microns, for example, that might be a useful guideline?
I think practically speaking, Tom, the idea would be, the amount that would be respirable needs to be below theamount that we could reasonably anticipate would produce an adverse response in the lung.
MR. GREMILLION: I guess, how would cumulative effects play into that? Because if a lot of different
manufacturers have products that, on their own, aren't making -- or contributing to an adverse effect, but people areusing multiple products that have small respirable quantities, since together they could produce an adverse effect. I
wouldn't know how to calculate that if I was a manufacturer.

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DR. LIEBLER: Right. And the manufacturer, in that case, couldn't necessarily anticipate that Ms. Smith is using
this face powder, and this spray, and this other thing; whereas, Ms. Jones is only using the face powder. That's
almost beyond our purview.
If we, again, go back to the example of the botanicals and sensitization, we can specify, within a particular product,
formulated to be non-sensitizing, to avoid stacking up sensitizing ingredients to a level that produces a response.
But I don't think that really addresses the possibility that using six different botanical products, over the space oftime, couldn't produce a response. In other words, I think there are just some things that are just beyond our ability
to control.
MR. GREMILLION: I guess with the sensitizing, it seems like that's not analogous because it's either, there is areaction or there isn't. But with something respirable, it's like you have to have a lot of something to cause an
adverse reaction from breathing it in.
DR. LIEBLER: Both of these phenomena are dependent on exposure and dose.
MR. GREMILLION: I see that in very broad terms, but it seems kind of like a qualitative difference between
sensitizing and respirable.
DR. HELDRETH: As it's clear, this would be a new type of conclusion that the panel's putting forth, and that's
certainly the panel's prerogative to do that. However, historically, I think the way that we would have handled this,in a conclusion, is to say safe with whatever qualifications for other uses, but that the data are insufficient for use inthings like sprays and powders.
DR. MARKS: I'd like Ron, Ron, and Tom to address it. Our team felt that -- at least, if I interpreted our discussion
correctly yesterday -- was the inhalation concerns were not relevant to cosmetic use. Did I get that right as thebottom line?
DR. SHANK: Yes.
DR. MARKS: So, after this really robust discussion and concern about sprays and such for cosmetic use, I don't
know whether, Ron Shank, you want to address why we felt that that wasn't a concern?
DR. SHANK: The inhalation toxicology data, in the report, was aimed at looking at these silicates into the lungpurposefully. It wasn't the kind of study that would apply to cosmetic use. On the other hand, rather than puttingthat into the conclusion, that they’re formulated to be non-respirable, we have to see what the boilerplate is going to
be for aerosols. Because that's how we've usually handled it in the discussion, that the use is infrequent and, for themost part, large particles which are not inhaled. We've now put it into the conclusion.
If we start -- first, we add the formulated to be non-irritating; now, formulated to be non-irritating, formulated to be
non-sensitizing. Now we're going to go, formulated to be non-irritating, non-sensitizing, non-respirable. Two years
from now, we're going to be formulated to be nontoxic, and then we can all go home. I don't want to be facetious.
DR. LIEBLER: Ron, you're messing with my plan. I really wanted to get home.
DR. SHANK: I think it's dodging the issue. We've done it with non-sensitizing because it's usually been mixtures,
where you have botanicals; and you have so many things it's hard to pick on any one chemical within the mix. Dr.
Belsito explained the non-irritating. That's strictly formulation dependent. That makes sense. I think, I would
rather handle this in the discussion and not put a restriction in the conclusion.
MS. BURNETT: If it helps the discussion at all, the original discussions for the 2003 silicates report, and the 2009
silica report have a respiratory component to the discussion section. If you want to look at that language, that's PDF
Page 92-93, if any of that language can be reused or amplified.

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DR. BERGFELD: Ron Hill.
DR. HILL: I still think that Dr. Liebler's idea is worth some serious and strong consideration, first of all. Secondof all, the definition of respirable is a little bit shaky. I mean, we have some idea about that; however, in principle,with these given the idea that we are talking about solid particulates, I presume in all cases, at least we have an ideaof what we're talking about. We're not talking about evaporating droplets, except as maybe in propellants, forexample, in a pump spray.
My fundamental problem with this report, as it sits right now, is we've got 13 new ingredients in there for which I
can't answer the question beyond the basic dictionary description, what is this stuff? I think that if we’re doing anamended report here -- and I asked the question yesterday, is this an amended report or is it a new report, because
we've got a number of ingredients that we can't answer the question, what is this stuff? So for me, until I get
answers to that, it's insufficient on all of those that we don't have those answers.
Because that relates to, it's a difference between crystalline silica versus amorphous silica with fine (phonetic),
versus the sorts of things that we actually see in cosmetic ingredients. Those are three different forms of silica.
Again, I mentioned that as a chemist working many years, where almost on a daily basis, I was filling silica columns
where we had to be very sure not to breathe those fines; that was a very different situation than in a cosmetic
ingredient. In most cases, we know if it's face powder, they already present as higher agglomerates; there's notgoing to be fines in there and we don't have an issue, speaking to the cumulative problem.
But we've had a lot of discussion. We had a very robust, long discussion about the respiration issues, yesterday, towhich we in the end didn't come with any firm conclusions other than some lack of information that we still need.
DR. LIEBLER: I just want to say this one thing. My inclination, originally going into this was right where Ron
Shank is, that these are not respirable. But then I'm faced with the issue of saying, because why? What are the datathat support that assertion, that that's not relevant to cosmetic use? That's where I felt I was tripped up. That's why
I'm searching for an alternative way to deal with it.
I think you could also handle this in the discussion. If you wanted to say safe as used but, in the discussion, veryclearly point out the issues and the unknowns, and the fact that this is something that manufacturers would need totake into consideration in the formulation, I can live with that too. But as again I was struck by the similarities, even
if they're not complete to the formulated to be non-sensitizing, and that's why I made this suggestion. So, I'm glad
we've had some discussion about it.
DR. BERGFELD: Paul and then Don.
DR. SNYDER: First, I’m going to qualify by saying, I'm not an inhalation toxicologist. But my comments are
related to the fact that inhalation toxicity can be localized. It can be in upper airways, it can be all the way down in
the respiratory tract. The issue with respirable particles is that they get deep into the lung, and now we have a
different relative exposure for potential systemic toxicity, that may be different than oral, than pharyngeal, othermechanisms by which there could be exposure.
So, I think we're kind of -- we're not fully understanding the toxicology. And, Curt, maybe you could elaborate on
this more. So, the physical properties of the formulation drive where it's going to go, and how deep it's going to go.
It's not chemistry, it's not biology, it's just the physical properties of a thing. So we've always used that as a basis tobe safe, to be confident that even some incidental exposure through discontinuous use or whatever, is not likely
going to result in any significant toxicity. I think that's very different than saying non-respirable.
Because all of a sudden, now, if we have a conclusion that says non-respirable, because it has an aerosol use, allprevious report that we've had aerosol use, and we don't have non-respirable in there, are now not compliant withuse, right? I think that really opens up a huge can of worms, that I don't think we need to open. Because the oldreports clearly state we had data to support that they're non-respirable; and we're not concerned about systemic
toxicity from being respirable.

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DR. BERGFELD: Don and then Curt.
DR. BELSITO: Just looking how we handled it before, the final sentence, in the discussions, said that the panel
considered that any spray containing these solids should be formulated to minimize inhalation. It's almost like a
restriction that could also occur in the conclusion.
I guess my concern -- and I brought this up with Alexandra yesterday -- is that -- and I'm, again, not a respiratory
toxicologist, nor am I a spray physicist or physical engineer. But I think we've been operating under the assumptionthat there are hairsprays and there are pumps. Now, we're being told they are different types of delivery systems.
There's some spray tanning delivery system that's different. There's liquid spray make-up that's different. And we
don't have any idea what the range of particle sizes that those would deliver.
One of the things that I asked for, was that we have someone come to the panel, who understands spray delivery
systems, and tells us a little bit about, you know, okay, here's the average particle size from an underarm deodorantpump. Here's the average particle size from a hairspray. We could maybe get to this issue by understanding what
type of delivery system is most likely to generate the smallest number of aerodynamic particles.
I think that our assumptions that there are just two types of sprays and, you know, pumps deliver a larger
aerodynamic sized particle than a hairspray, there are other spray delivery systems that we don't have information
about.
DR. HILL: And the other -DR. BERGFELD: Curt and then you can comment.
DR. KLAASSEN: Well, I think we've discussed most of the issues here. I guess I would -- the bottom line here forthis report, I think, I would be more in agreement to keep it the way it was in the previous addition; that isemphasizing the possibilities here, but not putting it in the final conclusion.
DR. BERGFELD: Tom and then Ron.
DR. SLAGA: I agree with Ron Shank and Curt. I think we have to go on what we did before. And just have that,and maybe add a little bit more to the discussion that there is some little concern. But I would not put in the
conclusion.
DR. HILL: Yeah, I was just going to point out, again, that one of the chronic -- no pun intended -- issues that wehave, is making sure that we distinguish between solid particles of things like zeolites and the like, silica, and liquid
droplets that have compounds in them. Sure, they may become solid briefly, as they're flying through the air and thesolvent is evaporating, but can redissolve in the lungs; and we have -- well, we don't have any toxicology related tothat.
It seems like in all these discussions of particle sizes -- and I mentioned, although technically, there is no reason thatwhen I think of a droplet, I think of liquid, when I think of particle, I think of as a solid, which is actually notaccurate, you could have a liquid particle. But anyway, we have this muddling of things.
In this particular ingredient set, I presume, we're dealing with things that are solids across the board. So, I want togo back to this particular ingredient and make sure we're thinking in that terms. Again, we have 13 things in here
where all we have is the description and still no, what is this substance? So, I don't know why we're not insufficientfor getting information about the properties of these compounds.
DR. BERGFELD: Thank you. Dr. Marks, you had a motion with not seconded. You want to -MR. GREMILLION: Could I ask. There's this letter from the Women's Voices for the Earth that --Distributed for Comment Only -- Do Not Cite or Quote

Clays – Expert Panel for Cosmetic Ingredient Safety Meeting Transcripts

DR. BERGFELD: We're going to address that under aerosols. Thank you. Do you want to propose a motion?
DR. MARKS: I'll address the letter in a minute. I want to get to the discussion. I'll repeat the motion that our teamproposed. That's that this is a tentative, amended report, 40 ingredients with a safe when formulated to be nonirritating conclusion.
DR. BERGFELD: Is there a second? Seeing none, is there another motion?
DR. BELSITO: I like Bart's idea of saying the data is insufficient to determine the safety for products that could be
inhaled. I'm still very concerned that I don't understand the technology of sprays, and the size of particles that canbe delivered.
DR. BERGFELD: Is there a supporting motion for this, go insufficient?
MS. BURNETT: It would have to go as an insufficient data announcement with what you need specified.
DR. BELSITO: What we need specified is the range of particle size in products that are used in sprays and facepowders, that one would expect in terms of how these are being used.
DR. BERGFELD: Would you need the delivery systems?
DR. HILL: If you're asking for range of particle size, that would be implicit as far as I'm concerned.
DR. BERGFELD: Okay. All right. So, the motion has been restated. Is there a second?
DR. MARKS: I want to hear Ron Shanks comment.
DR. SHANKS: I think the issue of inhalation toxicity with these ingredients can be handled in the discussion, as
we did before, and not in the conclusion. We all agree it is a concern, and I think it is how to state the conclusion.
If we start putting it in the conclusion now, then we have a huge back load; every time there is a spray or aerosol,
we're going to have to put this into the conclusion, because we don't have a lot of data for every ingredient. That's
why we have this precedent document that discusses this in great detail. Particle size is not the only thing that
determines pulmonary exposure.
DR. LIEBLER: I'd just like to say that I appreciate my collegues' thoughtful consideration of my suggestion. I
think that it's not going to fly, and I've heard a lot of good reasons why it probably shouldn't. I still think the choice
between us right now, is whether to say safe as used, and we'll try and craft the discussion to deal with it; or whether
we should say insufficient, at this stage, for this report, and see if we can squeeze out more information that could
end up helping us inform our discussion later on anyway. So, that's why I kind of lean in the direction that Don is
proposing, at this point.
DR. BERGFELD: Is there a second to Don's motion?
DR. MARKS: Second. I’ll withdraw our team's initial motion.
DR. BERGFELD: Well, it wasn't seconded, so it did not go forward. So, we're going to have any otherdiscussion? You want to know -MS. BURNETT: In addition to the range of particle size, for products that are sprays and powders, what additional
items would you like in the IDA?
DR. BERGFELD: Do you want to request a characterization of the chemistry?

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DR. HILL: I do want information about these ingredients.
MS. KOWCZ: Can I just make one comment?
DR. BERGFELD: Yes. Alex.
MS. KOWCZ: Well, we just really want to know, exactly, what is the ask from the panel?
DR. BERGFELD: Christina has the list, we'll let her read it.
MS. BURNETT: Range of particle size for products that are used in sprays and powders. And chemical
characterization of the new add-ons.
DR. HILL: The ones for which we don't have data, new or existing, honestly.
DR. LIEBLER: So, chemical, physical properties is thin, it’s just silica and hydrated silica; it’s none of thezeolites, for example. Method of manufacturing is just silica and hydrated silica. Those are synthetically produced.
I don't know, is everything synthetically produced now? Or is some of it mined? Composition impurities, again, isjust silica. This is a big report with a lot of ingredients, and we've got just the tip of the iceberg.
DR. HILL: Well, this particular report, that was an issue I had yesterday, is relying on four or five previous reports.
There's a significant number, I think, they're referencing, but it's not really brought in and captured. What I wrote inhere was there were a lot of x's in the box, indicating we had data that don't directly show up in this report.
So really, some way of doing data capture without having to bring over all the language and all the information fromthose previous reports. I mean, we're relying on those. And whether information exists in the previous reports, justat some -- I don't know if there's any way to briefly summarize, in a table or something, to indicate what's there in
the previous report so that the reader could at least use this in some self-contained fashion.
For the new ones, where we don't have information -- and there are things that are mined. There are zeolites that aremined, there are clays that are mined, there're things that are not synthetically produced, but they may be processed.
I don't necessarily know what that processing is, honestly, in each of those cases. But at least some sense of what
the composition of the things are, and maybe the source, if it's applicable.
DR. BERGFELD: So, a clarification on this request; physical chemistry of the unknown ingredients, are we
adding methods of manufacturing impurities since we're asking?
DR. LIEBLER: Yes.
DR. BERGFELD: Anything else?
DR. HILL: Let's see what we get. If we don't get it in some case, and we decide if it's important or not.
DR. BERGFELD: Okay. And then just an editorial that we go back and tabulate all those previous studies for thisdocument. Okay. Don and then Monice.
DR. BELSITO: Just to point out, I went back and looked at concentrations of use. For instance, silica, in anunderarm deodorant, can be used up to 10.4 percent, which is not a negligible amount. And we know that underarm
sprays will have lower aerodynamic particle size.
MS. KOWCZ: Can I just mention that these are amorphous-hydrated silicas, the ten percent that you're talking
about. So, it is dissolved in the formula.
DR. BERGFELD: Thank you.

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DR. BELSITO: That kind of information can be brought into the document?
DR. HILL: We have had past presentations on that, but then the situation is different. If it's in a spray, the particles
can potentially evaporate, versus it's in a solid underarm deodorant.
DR. BERGFELD: Okay. Monice?
MS. FIUME: Just to clarify for the information on the particle size and for the ingredients; and, Alex, maybe this iswhat you were getting to. Is it all ingredients that are used in sprays; or are there specific ingredients from that listthat you would really like to see the particle size information on? Is there more concern for some than others, or allthat are used in sprays or powders?
DR. LIEBLER: I think we should ask for all that are used in sprays and powders. That maximizes our opportunity
to get relevant data.
DR. BERGFELD: Thank you. Any additive remarks?
DR. MARKS: Yes. Yesterday we were given a Women's Voices of the Earth letter. Our team decided not toreview that letter yesterday. We postponed it until the next meeting. It did elicit some discussion of getting Wave 3,
Wave 4, and Wave 5's, at very short notice, and being able to review those thoroughly and think about our
responses. I just bring up that point about yesterday. Don, I don't know whether your team felt comfortable
reviewing it, but our team did not. Team members, do we have any other comments? Ron?
DR. SHANK: No, I think that the CIR can respond immediately; but I think the panel needs some time to consider
how we want to respond. And we haven't had enough time to do that.
DR. BELSITO: Well, I think we discussed it, which is part of the reason why we've come to this conclusion, that
we need time to digest what she said and to get a better understanding of particle size in these sprays. So, that was
our response to this letter, that at this point we're going insufficient. We will consider her points and come backwhen we relook at the document.
DR. HELDRETH: On our end, we will make sure we respond to her and let her know exactly what we're doing.
Then the next iteration of this report, when it comes back to the panel table, will have this letter and our summaries
in there. And any input we get from others about the content of the letter will be included there as well.
DR. MARKS: And then the only other comment I had -- and, Don, you can respond to this if you want. There waslittle sensitization data with Kaolin used up to 53 percent on leave-ons, and silica at 82 percent on leave-ons. But
there's no alerts in the clinical literature that would suggest these are significant sensitizers. So, I felt we could moveon and not be concerned about the sensitization of these ingredients.
DR. BELSITO: I agree.
DR. BERGFELD: Paul, did you have something to say? I'm going to call the question then, to move the questionof this is going out as an insufficient data announcement. All those in favor? Unanimous. All right. Thank you for
that, again, very robust discussion.

APRIL 2019 PANEL MEETING – DRAFT TENTATIVE AMENDED REPORT/TABLED
Belsito’s Team Meeting – April 8, 2019
DR. BELSITO: Okay. Silicates. We've got a lot of information and I thought it was okay, but it's not my area ofexpertise. We asked about molecular size and we got all these graphs, M, N, R, P, Q, which were 10 microns, but

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then we're told that became agglomerates and it gets to larger than 100. And I just looked at them and said okay.
I'm not concerned about them with skin, so I pass all of this discussion on to you three.
DR. LIEBLER: So going to those pie charts, a lot of those pie charts said that -- up to 50 -- did I read it right? Up
to 50 percent were less than five microns?
DR. BELSITO: Yeah. But those were like all the original ones. And then we get this thing at the end that says,
okay, that's their particle size. But then when they're put together, they agglomerate and they're all greater than 100
microns, is the way I read it, but I'm not sure. Again, as I said, it's not my area of expertise. So maybe we can havesome comments from -DR. SNYDER: And then also the grouping, because he mentioned the amorphous -- synthetic amorphous,synthetic silica aluminates, crystalline and then natural. I mean, what are the major groupings in this report? Do
you have access to our document?
MR. JURD: I'm not sure which. Are you looking at like the phase three, the one that came through?
DR. BELSITO: We’re looking through the CIR document.
MR. JURD: Yes.
DR. SNYDER: So we have a whole list here from activated clay all the way to zirconium silicate. And so if you
look at that list, what are the high-level classifications that would capture all of those?
MR. JURD: I'm not sure about how they were lumped and how everything was kind of laced together. I can tellyou, like synthetic -- I mean, there's a big difference between the synthetic versions and naturally occurring. So
synthetic amorphous silica is created from primary particles; very, very small in size. They agglomerate and thenaggregate. So, once they get to the larger size, it takes a tremendous amount of energy to separate those.
What the materials that are put on the market, for the most part, are larger particles, you know, between I'm going tosay 10 and 80, 90 microns, type size, not in the nano range. The primary particles are typically in the nano range.
There's a lot of focus on that in other areas, but those do not typically exist, or in large, easily measurable -- one ofthe difficulties the industry is having right now is actually measuring materials at the very, very small level.
And a lot of this is due to the definitions that are out there by a lot of various regulatory agencies looking at, youknow, what defines material like nano in Europe. Silica, by at least one group, has been defined as nano structured,
not a nano material, because it's composed of lots of little small things glued together.
DR. LIEBLER: So are silica and hydrated silica the only synthetically produced ingredients on our list, which on
our document is PDF page 93?
So our methods of manufacture section, which is right after this, is at this point somewhat incomplete. And it does
indicate that those two, silica and hydrated silica, that are used in cosmetic products are synthetically produced. But
it doesn't give much information about the production of any of the others.
MR. JURD: I know for a fact that a lot of these are synthetically manufactured. We manufacture ourselves a lot of
the silicates, sodium, the magnesium aluminum silicate is synthetically manufactured, along with a number of theother ones, potassium silicate. Not that I'm aware of, or anybody that I know of, has informed me that they're usedin cosmetic products, but they are -- they can be synthetically manufacturing.
DR. LIEBLER: So two of the issues that we have to deal with are the particle size, and the control ofcontaminants. And of course, particle size and control of contaminants are under full control in the synthetically
produced materials. But the materials that are mined and then worked up somehow are not, or not as controlled.

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And there are some of those on our list, I would imagine things like Fuller's Earth and activated clay and zeolites,
although I don't know for sure.
So we have really inadequate information to assess whether these all go together in the report, just from thestandpoint of how they're produced.
DR. BELSITO: That's one of the issues that Women's Voice raises in their last paragraph.
DR. LIEBLER: Right. And the other issue about the mined material versus the synthetics are that the minedmaterials may contain some crystalline silica. I think you mentioned that earlier.
MR. JURD: That is -- it depends on the purity, where it is and -DR. LIEBLER: Exactly. That's much harder to assess and control, but it's an issue that we need to be concerned
about for safety. And so, you know, there are a number of other points made in this memo to Bart from the Scienceand Support Committee that I'm not sure I agree with, but it sure would be good for us to have enough information
to make some judgments about which things actually go together in the report based on the composition andcharacter, physical chemical characteristics of the ingredients, relevant contaminants that are particularly healthconcerns. And once we have that information, then perhaps we can take a swipe at the issues that are raised in thismemo.
So, that's something, at least as a representative of industry, maybe if you can help disseminate that information
back. Because I think our description of method of manufacture for these is really incomplete to the point that we
can't make the assessment we're being asked to make.
MR. JURD: We can provide data based on what our members actually manufacture.
DR. LIEBLER: Correct.
MR. JURD: I can't go beyond that.
DR. LIEBLER: Well, that's all we care about. That's all we care about because those are the cosmetic ingredients.
So silica products that are used for things other than cosmetics we don't care about, and we don't need to know that.
But we do need to know about the ingredients that are used in cosmetics.
MR. JURD: We can definitely provide information. I think you've got almost everything on the silica, with someof the other reports. I don't know if that's a true statement. I mean, you might have to confirm for me.
We definitely have good contamination materials, you know, byproducts, impurities. Most of the impurities comein low levels of metals, primarily, from sodium silicate or sulfuric acid. Silicates, pretty much the same thing; lowlevels of metals, very, very low. And then leftover raw materials, sodium silicate, that sort of thing.
MS. BURNETT: Some of the method of manufacturing is in original report. Since this is an amended -- reopened
amended -- review. The clays, it talks about being strip mined.
DR. LIEBLER: But the original report wasn't published.
MS. BURNETT: For silica and hydrated silica, this is -DR. LIEBLER: That wasn't published.
MS. BURNETT: Yeah. So that one wasn't published. But if you go to PDF page 155 from the 2003 silicate report,
it also includes like kaolin and attapulgite.
DR. LIEBLER: Zeolite.

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MS. BURNETT: Bentonite.
DR. LIEBLER: Because many of these things are still used, as our survey indicated. Yeah, the method of
manufacturing, the current report suggests that there's not much known, and there's actually a lot known.
MS. BURNETT: I can pull that -DR. LIEBLER: So we need to somehow find a way to bring that in, or at least to summarize it.
MS. BURNETT: I will make sure I pull that in.
DR. LIEBLER: Okay. It could be another table.
MS. BURNETT: Okay.
MR. JURD: I guess what might be a little bit confusing, too, is most of the synthetic silicates, along with synthetic
zeolites, you have naturally occurring forms too. You're running into that, I think, across the board. Whether or notnaturally occurring material is used for the same sort of applications, I don't know.
I mean, zeolites is a really good example. You know, there's a lot of those manufactured for a broad range of uses.
And they're lumped into a general category. I mean, zeolites are defined by the EPA as a statutory mixture. So,
silica alumina, cations and anions; so it can be literally hundreds of different types of materials, which can be achallenge.
DR. LIEBLER: So in the current report version, kaolin and magnesium aluminum silicate are listed as containing
quartz or crystalline silica. I don't think I'm overlooking any others, unless some of these mineral names are also
crystalline silicas but don't explicitly indicate so.
So that's an issue we'll need to address by knowing the levels of impurities to be able to deal with it in our
discussion.
DR. BELSITO: But we've done it. So that's an insufficiency.
DR. LIEBLER: Right, yeah. I'm putting this in legal terms. But yes, it's -DR. SNYDER: So, essentially, we still have the same data needs that we had originally.
DR. BELSITO: Well, we need particle size for silica and silicate, don't we?
DR. SNYDER: Yeah.
DR. BELSITO: Do we need more data on that?
DR. SNYDER: I was thinking more of the composition and impurities, Dan’s point.
MR. JURD: For the silicates?
DR. BELSITO: So, basically, we get rid of the first request, which is particle size, for silicate and silica ingredientsthat are used. We asked for hairspray and powder formulations. We really didn’t specifically get that. We got
particle size, but not for hairsprays. And we're still not done with the respiratory boilerplate, because we didn't sign
off on that. Right? So how do we handle that? We really don't have the first data need either.

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DR. LIEBLER: So it sounds like we have some of the information we need. It just needs to be brought into thereport from the previous reports and isn't here yet.
DR. BELSITO: No, we don't have impurities or chemical characterization. We have method of manufacture,
which is pretty crude. Bentonite, mined ore bentonite, is processed to remove grit and nonswelling materials.
DR. LIEBLER: Right. But Christina just told us that the previous reports have a lot of that in -DR. BELSITO: I'm reading the prior report. This is page 155, Method of Manufacture, from the prior report. It
has data in there. I mean, it has stuff in there. But are you satisfied with, "The mined ore bentonite is processed toremove grit and nonswelling materials"?
DR. LIEBLER: No.
DR. BELSITO: That's what we have for bentonite.
DR. LIEBLER: So we're still insufficient. Okay. Fair enough.
MS. BURNETT: Dr. Liebler, could I ask you, on the data that we received from SASSI, all those different graphs,
should that be brought in the report? And if so, what would be a good way of presenting that data?
DR. LIEBLER: I think those data could be presented in the form of a few sentences.
MS. BURNETT: Just a few sentences.
DR. LIEBLER: Because first of all, those particle size distributions -- actually, as I recall, they don't name aparticular silica form, do they?
DR. BELSITO: No, they're A, B, C, D, M, N, P, Q, R.
DR. LIEBLER: So just Product A, Company B, and distributions. So what you could do is indicate that industry
reported X silica particulate size distributions that ranged from -- medians ranged from X to Y. Or the median was
X and the ranges were from A to B. And that's about all you can report. And if we can't associate these with any
particular silica forms for any of the ingredients in this report, that's all we can say. It becomes a piece of
information that's worth a couple sentences.
MS. BURNETT: Thank you.
DR. BELSITO: So this was a draft tentative amended. So we're now saying that we really got none of the data that
we asked for, except for some particle sizes on silica and silicate, but not as used in sprays and powder formulations.
But then we heard that when they agglomerate it would take a tremendous amount of energy to separate them.
So, I guess if we combine that statement, we could say that they're not respirable. Could we?
DR. LIEBLER: So they're mostly not respirable. I mean, based on those distributions, it appears that they're not,because the -DR. BELSITO: Even the small ones will agglomerate, we're told, to over 100 microns. Because some of them,
you know, M, N, R, P, Q, were 10 microns.
DR. LIEBLER: Right. Yeah. My impression from looking at that summary was that they were referring to theparticle size distributions of the final reduced particles which are already agglomerated. So you get -DR. BELSITO: Is that true?

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MR. JURD: That's -- yes.
DR. LIEBLER: So you get the precursor molecules. They aggregate into aggregates. And then aggregates form
agglomerates or agglomerate. Right?
MR. JURD: Correct.
DR. LIEBLER: So aggregates are small-ish, agglomerates are bigger. And that's the final form of these prior toincorporation into any cosmetic formulation.
MR. JURD: Correct. Yeah, you can break apart the smaller pieces without -- well, some amount of energy isrequired. But once they are at -- form the larger particles?
DR. LIEBLER: Right.
MR. JURD: They're pretty robust.
DR. LIEBLER: Too many bonds.
MR. JURD: Right.
DR. LIEBLER: Too much energy.
MR. JURD: Right.
DR. LIEBLER: Whereas the small particles are smaller, and there's less energy.
MR. JURD: But these all are, you know, the way that it happens, we can't discount that there isn't a tail of smallermaterial.
DR. LIEBLER: Well, that's what I'm referring to also. It's almost entirely not respirable, but a tail is a tail; and it
includes, you know, an indeterminate number -- well, not indeterminate. You can estimate the percentages.
DR. BELSITO: So then, when we're looking at -- like on our PDF from Wave 2, page 73, where we have a
distribution curve, and the particle size seems to be peaking at around 7.5 microns, that is what's actually being
supplied to the manufacturer?
Or does that further agglomerate and what's being supplied to the manufacturer is going to be over 100 microns?
Because my understanding of reading further on was even these smaller ones will aggregate to larger particles. But
are you now saying that whatever sample R was, was nanometers, and it's aggregated up to 10 microns?
DR. LIEBLER: No. If you -- I'm paging up in this document, past all these particle distribution graphs, to the text-- or there's a figure that shows the process?
DR. BELSITO: Yeah.
DR. LIEBLER: I remember seeing a figure for -- I think it was the nanoscale material, voluntary submission -DR. BELSITO: Was it figure three, structural difference -- no.
DR. LIEBLER: The voluntary submission document. Ah, it's in -- hang on. Just scrolling through it.
DR. BELSITO: Wave 2 or?

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DR. LIEBLER: It's in Wave 2, the Wave 2 document. I'm getting close.
DR. BELSITO: Is it page 91, reactor feed?
DR. LIEBLER: Yes. Yeah, page 91. So I'm assuming from the description -- so page 91, the figure 1-4 for is thegeneral structure development sequenced during SAS manufacturing and reactor feed has the precursor moleculesthat form nuclei, which are individual molecule particles, which form primary particles, five to 50 nanometers,
which then form aggregates. And that little purple cone shows that that's all happening within the spray zone, I
guess.
And then I interpreted this is that these aggregates are forming the agglomerates as the aggregates are being formed.
And this is all happening in the reaction vessel, and that it's not happening as -DR. BELSITO: But some of the agglomerates are less than 10 microns.
DR. LIEBLER: Yeah. One to 250 microns, it says there.
DR. BELSITO: Right.
DR. LIEBLER: And our particle size distributions go down to about one before they appear to zero out.
DR. BELSITO: Right.
DR. LIEBLER: And then the one you just pointed to have a median of -DR. BELSITO: 7.5 almost.
DR. LIEBLER: Yeah. Anyway, so -DR. BELSITO: So these are small, even when they agglomerate.
DR. LIEBLER: Yeah. But that's the version of the particle, that's one of the smaller ones. Because some of these-DR. BELSITO: I understand, but we don't know whether that particle is used in or in a pump or spray. We don't
know what the particle is. So then -DR. LIEBLER: The other unknown is when you put it into a cosmetic ingredient, if those agglomerated particles
form anything larger, by combining with other ingredients in the formulation.
DR. BELSITO: And then how strongly do they agglomerate. And then what happens when you spray them out ofa hairspray or whatever other sprays they're in?
DR. LIEBLER: Yeah, we don't really know -DR. BELSITO: So, in essence, all of our data needs that we had asked for before are still unanswered. Because we
now know that some of the agglomerates are down to 10 microns. And we also know that we don't know anything
about what happens in terms of those that are used in sprays and powders. We don't know which ones are.
And then the next question becomes all the ones that are naturally mined, like bentonite and clay, do we keep thosein the report? I mean, this is this is WVE's last question to us. Is this grouping correct?

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DR. LIEBLER: I think it's a fair question. I don't know how much better characterization of those we'll have toallow us to make that determination. We've been reporting on these for years.
DR. HELDRETH: Right. So, just looking at this and looking at the history of this, we had ingredients like
Fuller’s Earth, and, you know, sodium magnesium silicate, already in the original report together. And it's time toreview all of those ingredients again.
So really it comes down to two options, if we want to start splitting things up, if we can figure out which one's go inwhich report, or split them up within the report to make sure that there's clear margins between them saying, youknow, we don't want to look at these together. So, I mean, either option -DR. LIEBLER: These might be like algae.
DR. HELDRETH: Right.
DR. BELSITO: Red, brown.
DR. LIEBLER: Yeah. But I mean, we have -- it sounds like we may have a significant enough repertoire ofsynthetically produced silica ingredients that might constitute a report on their own, for which -- well, we'll at least
have the data on method of manufacture and composition and -DR. BELSITO: Particle size.
DR. LIEBLER: Particle size. We won't set aside the issue of is the particle size a posed risk or not, because it
sounds like that might be one that's going to be hard to definitively determine. But then we will separate out thesynthetically produced materials, which have certainly greater certainty about their composition and impurities -DR. BELSITO: Well, if we could separate those out, or basically take the silica and silicates and anything that you
think is actually related, could we not come to a conclusion even in the absence of our data request for aerosolized,
just as we do with sensitization, since we know that some of them are down to respirable range, and some are well
above respirable range.
DR. LIEBLER: Right.
DR. BELSITO: Something to the essence that, you know, should be formulated not to be respirable.
DR. LIEBLER: Respirable, yeah. I think we may have to do that, because the one other thing that those
distribution figures show us is that there's a great variety. There's, you know, ten-fold variations in the medianparticle size, and the low-end tail is going to be dramatically different for the respirable fraction, between thesedifferent particles. And that's before you even put it into a cosmetic product with other stuff in it.
DR. HELDRETH: So that would constitute a new type of conclusion for the CIR Expert Panel to say, "when nonrespirable." Comparatively, though, other types of conclusions that the panel has come to often look more towards
to the product itself. So maybe we don't have enough information to say anything about an aerosolized product, or aspray product, or a powder project.
And so it may be easier for a formulator to read the conclusion of the panel if we're saying we don't have enoughinformation and say it's safe -DR. LIEBLER: So the data were insufficient to support the safety in sprays or products in which these ingredients
may be respirable? Or sprays and -- powers and sprays. They’re all powders and sprays.
DR. HELDRETH: Sprays or loose powders or whatever ones you think where the immediate problems.

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DR. SNYDER: We don’t know that it's insufficient; we know if it’s less than 10, they're respirable, and certainly ahazard if you inhale these.
DR. BELSITO: Right.
DR. HELDRETH: I mean, we just talked about how now we have to write a -- you know, something
what we mean by non-sensitized, nonirritating --to explain

DR. SNYDER: I get your point. And it sort of gets to -- both are similar responses to the problem. One requires us
to introduce a new type of conclusion that we haven't used before. And the other allows us to use a type ofconclusion we've used.
DR. BELSITO: We're told they are used and pumps and sprays. Okay? And I think we're also told that there aresome of them out there where even before they go into finished products, they're greater than 100 microns.
DR. SNYDER:

Less than.

DR. BELSITO: No.
DR. SNYDER: Oh, greater than.
DR. BELSITO: But there are also others that are greater. And if it's those that are used in pumps and sprays, we're
not concerned. If it's the ones that are 10, we are, potentially, right?
DR. LIEBLER: Correct.
DR. BELSITO: So we have data to suggest that some of them can be used. Just as with irritation, we have datathat when you take an acid and you neutralize it, it's okay. So if you put salicylic acid at 20 percent, but then you
neutralize it down until it's all a salicylate salt, we don't really care. So, you know, “formulated to be non-irritating”
is something we came up with, because we realize there are so many variabilities.
So when you're looking at this, you know, I don't think the data are totally insufficient to say that they can't be used
in, you know, in a product that could be respirable, you know; because some of them can be, based upon theassumption that -- I mean, if you look at A, B, C, D, E, F, I think you get up to M before you get them dropping
down into a respirable range.
So, I mean, there are 12, 13 right there that could easily be used in a product that is a pump or a spray. And then you
get M, N, P, Q, R, which could be an issue.
So I would actually feel more comfortable saying that there are silicas, silicates out there that aren't an issue andthere are others that could be. And therefore, “when formulated to be non-respirable” is a reasonable conclusion.
Because if we say insufficient, you know, then a company that is using these, and they're using one that has adiameter above 100 is, you know, in two years in trouble, right?
DR. LIEBLER: Yeah, no, I mean, I agree. So, doing what you were suggesting, Bart, just floating the idea out
there, that would essentially exclude perfectly reasonable products -- or perfectly reasonable ingredients for use inpumps and sprays. And really, what we need to do is in pumps and sprays, or other potentially respirable products,
is reduce the respirable particles as ingredients.
So, just because we haven't ever done that conclusion before, doesn't mean we can't. There's a point at which we
hadn't done formulated to be non-sensitizing, and we did it for the first time. So -DR. SNYDER: My preference would be that we get some data, because we can have an old report that states these
are all safe, even in sprays, because they're a particle size not respirable.

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DR. BELSITO: But now we have data that shows -DR. SNYDER: But now we have new data, so that's all a wash. That goes away. But what we don't have is we
don't have the distribution, those tails and whatever it is, because there's no doubt that even a small amount of thismaterial in the lungs is going to cause fibrosis and an adverse reaction.
So even though we have this distribution data, we don't have what -- those tails. You know, even in the products,
how much is that? Is that one percent, five percent, ten percent?
And so I think what we need to have is we need to have very specific composition data on all the ingredients that areused in the spray and aerosolized products, period. And we cannot make any determination of safety unless we havethat. And so -DR. BELSITO: Even if we put the caveat “when formulated to be non-respirable”?
DR. SNYDER: I know what Ron is going to say. He says, why don't we just write a simple conclusion, when
nontoxic, non-respirable, non-sensitizing. And so I think we can do a better job than that.
I think that if we're evaluating -- our standard has always been that we evaluate ingredients as used. And so we lookat those that are used in aerosols, and say, okay, yes or no? Do we have the data? And if the data is insufficient,because we don't know what that tail is, as far as how many particles are less than 10 microns and are respirable,
then we can just simply state that, and leave it at that. I'd like to get away from these bastardized conclusions.
DR. BELSITO: So let's say that we get a report and the individual ingredient has a tail where, as a toxicologist,
you're concerned about even the small amounts that would be respirable. But now when you put ingredient X intothat formulation of hairsprays with PVP copolymer, or whatever else is in the spray, you now get a molecule withnone of those tails.
DR. SNYDER: But they've got to give us the data then, in that formulation. I mean, I really need -- we have someto be science-based, data-based.
DR. BELSITO: I understand.
DR. SNYDER: Because it actually would be better for us to say that, in this instance, using this product, anaerosol, is unsafe, because there's a significant amount that's less than 10 microns and is respirable. I think that's abetter conclusion -DR. BELSITO: But how do we know that -- what in formulation?
DR. SNYDER: We have to have -DR. BELSITO: We just know that from the ingredient. Just like we know that -DR. SNYDER: Let's say we do the same thing with sensitization, we wanted concentrations in use, so we want to
see it with -DR. BELSITO: Sometimes we say that is a sensitization hazard. And it really depends what product type. This isgetting back to QRA. You can't just go by an HRIPT.
DR. SNYDER: I think we're getting a little ahead of the game here, because I think we've got to reopen this oldreport because clearly what it states as a conclusion is wrong.
DR. BELSITO: Right.

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DR. SNYDER: Okay? Because it says all product is not respirable because of particle size, use that as the bar; andthat's not the case now, because we know that they can be respirable.
DR. BELSITO: Right. Okay.
DR. SNYDER: So now let's go back and let's just reiterate that for aerosol use, we've got to have some of this data.
DR. BELSITO: Okay. But then we're reopening -- I can't keep straight where we are. But we reopened, we added
a bunch of stuff, right? Along with the reopening. Okay. So for silica and silicates, you're saying we need to know
particle size for those that are in pumps and sprays.
DR. SNYDER: I think it goes beyond -- you had some other -- composition use, right, for -DR. BELSITO: Can we go back? I mean, are we going to split this document into natural and synthetic? And do
two separate reports? I think that's -- you know, again, that's addressing Women's Voices for the Earth, their lastpoint.
DR. LIEBLER: I think we might as well do that. I think it would help us deal with the issue -- it will help us deal
with the issues of impurities and defining the compositions and particle size, or at least control knowledge of theparticle size.
DR. SNYDER: It goes to our premise that we always consider the chemistry and uses to group things. And it
would make more sense that the chemistry is probably different in a synthetic versus a natural.
DR. LIEBLER: Right.
DR. SNYDER: With composition of things. Right?
DR. BELSITO: Okay.
DR. SNYDER: So I think that makes sense to me initially. But I'm not at that level of a chemist and look at thishuge range of things, this list, and know is that -- or is there other appropriate subclassifications?
Because I mean, he said there's synthetic amorphous, synthetic silica aluminides, the crystalline, and then thenaturally occurring. So some of it -DR. LIEBLER: This memo from the CSSC basically says don't group things that don't belong together. But they
don't say what belongs together. Thank you very much.
DR. LORETZ: I think was it was the clays, the zeolites, the amorphous and silica, and then kind of anothercategory. But it was really that kind of concern that you're kind of talking here, because each has its own kind ofquestions. It was kind of trying get at that, that there was just too much in one place, and sorting it out was reallychallenging. So I mean, that's why we were in favor of separating -DR. BELSITO: So do you think that the idea of separating the synthetics from the non-synthetics is a good start?
Or are we going to get a lot of pushback on that too?
DR. LORETZ: Well, I just mean, I think the clays, the zeolites, I think there was a sense that those should be
separated within that. Then you need to separate naturals from -- I'm not sure. We hadn't discussed that. But I think
those categories would be a starting point where you would separate that.
DR. LIEBLER: Yeah, I mean, it's hard for us non-silica types to even have a hint that you would separate theclays and the zeolites until somebody said, "What do you mean you're not separating the clays and zeolites?"

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DR. BELSITO: So, basically, what we're talking about is taking silica and silicates and moving them into aseparate report.
DR. LIEBLER: Sounds like it.
DR. BELSITO: And then that would leave us with -DR. LIEBLER: Still a lot of other stuff.
DR. BELSITO: -- zeolite, attapulgite, bentonite, Fuller's Earth, gold zeolite, hectorite, kaolin.
DR. LIEBLER: Bentonite. Did you mention that?
DR. BELSITO: I mentioned bentonite. Montmorillonite, pyrophillite, zeolite. The zeolite in general. And so we'dbasically be just staying with silicates, metasilicates.
DR. LIEBLER: Hydrated silica and silica -DR. BELSITO: Yeah, just that. And then what do we do? Do we separate zeolite from clay from Fuller's Earthfrom bentonite from attapulgite? Or do we try and look at those in one chunk?
DR. LIEBLER: I think our suggestion is that we probably look at those in one chunk, unless industry returns to us
with additional reasons to unchunk them further. And they need to be good reasons. Because by making thisdivision, I think we hopefully address the issue.
DR. BELSITO: Okay. So basically, if I'm hearing things correctly, the silicates, silica, metasilicate are going to be
separated out. We're going to do a separate report. But we're still with an insufficient conclusion for all the reasons
we asked for before, for this entire group.
DR. LIEBLER: Mm-hmm.
DR. BELSITO: And then the remaining naturals, although I'm not sure that the zeolite -DR. LORETZ: I think that can be synthetic or mined.
DR. BELSITO: Okay. So we'll figure it out. We'll put it in the group for now, and see what happens in that othergroup that is not silica or silicate, and that will go out as insufficient for method of manufacture, impurities, particle
size; basically what we're asking for the silicates, except we're also going to be asking for a method of manufacture
and impurities, which we -DR. SNYDER: With an emphasis on particle size distribution for the aerosolized products.
DR. BELSITO: Right. If there are aerosolized products in those groups.
DR. SNYDER: Or powdered.
DR. LIEBLER: I'd like to come back to the issue of aerosolized particles and data, to address Paul's very strong
concerns here. Those particle size distributions we got would actually allow you to calculate the fraction that is
below any size threshold you want to calculate.
So it would be possible for a supplier of an ingredient to perform that analysis and provide that as part of their lot
characterization to the manufacturer of cosmetic products, so that they would be able to assess the median and thenthe fraction below wherever we want to designate as a respirable threshold.

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Then someone still needs to decide what's the limit of the amount of particles that are respirable in the product.
Now, that's probably not our call, because that turns out to be a specific number. Unless we have data that says, oh,
it needs to be less than X parts per million, or Y femtograms or micrograms or whatever. I don't know if we'll ever
have the data to allow us to do that. But those data coming from the manufacturer to -- the supplier to the
manufacturer of the cosmetic ingredient would allow them to assess the amount of respirable particle that they're
incorporating into their product.
And even though we don't say, you know, here's a cutoff number, we say that information should be considered.
And I would think that's one of the things you would be considering when you're deciding which silica toincorporate into your cosmetic pump spray or hairspray, something like that.
So we provide I think enough guidance, without being forced to say it has to be above or below this number. Does
that help from your perspective?
DR. SNYDER: Yeah, I mean, I think -DR. LIEBLER: And that allows us to still say “when formulated to be non-respirable,” but in the discussion wewould explain that that information can be determined; and that an additional consideration would be the effect of
the other components of the cosmetic formulation on the final particle size.
Because I think we all agree that could change the particle size, but it's impossible for us to say how much it's going
to change the particle size, and it's going to depend on what else is in the product.
DR. LORETZ: And also how it's being dispensed.
DR. LIEBLER: And how it's being -DR. LORETZ: Which can make a big difference.
DR. LIEBLER: So I still like the idea of saying “when formulated to be non-respirable,” but in the discussion
explain what information industry can use to document the particle size distributions of their products that they're
supplying to cosmetic ingredient producers, and then for the producers to consider in formulating products.
DR. BELSITO: Okay. So what I have is split silica and silicates from all the others, the data need has not changed,
and essentially the data need we needed for that was the range of particle sizes for ingredient to be used in hairsprays
and powders. So those have to be identified and get the ranges, but still come out with a conclusion formulated to
be non-respirable.
Then for all the non-silica silicates, basically, we're asking what we asked before, was chemical characterization,
composition, impurities, method of manufacture and source for those ingredients. And then if any of them are inaerosolized products, particle size and -DR. LIEBLER: Particle size distributions.
DR. BELSITO: Distributions. So basically what we asked for before, except we're splitting the groups. And thenwe'd be interested in the scientific committee’s feedback on the ones that we threw out, whether they can all begrouped or whether we should look at clay and bentonite and attapulgite and zeolite and any of those others
separately or as a group of sticky, earthy subjects.
DR. LIEBLER: Correct.
DR. HELDRETH: So for silica and silicates group, I didn’t hear you list method of manufacture or composition -DR. BELSITO: No. Just particle size and materials used in powders and sprays. That's it.

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DR. HELDRETH: What about the silica and silicates that are refined from naturally occurring minerals?
DR. SNYDER: That's why we still want to know the method of manufacture, as in the original request.
DR. HELDRETH: Because aluminum calcium sodium silicate is defined as coming from naturally occurring
minerals.
DR. BELSITO: Okay.
DR. HELDRETH: The other ones are vague, and you don't know if it’s synthetic -DR. LIEBLER: My original suggestion was the synthetics versus the naturals.
DR. HELDRETH: But we don't know which ones are synthetic.
DR. LIEBLER: Well, we'll have to find out. We know that two of the major use ones are synthetic. And we mayneed to find out which others -- well, we have to find out which ones are synthetic versus natural.
And again, my feeling from a chemistry standpoint is the synthetics, you know what went into it, you know theprocess, you know that it was pretty well controlled, they understand what they're making to very high degree. And
that separates those from the natural that are refined to some extent, but still have contaminants that are uncontrolled
and maybe not even well documented.
DR. BELSITO: Okay. So we're going to split the silica from the silicates or the silica/silicates from everythingelse. The data needs for the silicates are going to be method of manufacture and impurities -DR. LIEBLER: Particle size.
DR. BELSITO: For all of them essentially. Impurities will become more critical for those that aren’t synthetic.
Correct?
DR. LIEBLER: Right.
DR. BELSITO: But that's captured by method of manufacture and impurities. And then particle size and materials
that are used in powders and sprays. And then, despite that, we probably still say, “formulated to be nonrespirable.”
DR. LIEBLER: Right.
DR. BELSITO: And then for the others, the bentonite, essentially the same thing.
DR. LIEBLER: Do we want to see one report, then the other, or two reports in parallel at the same time? I'mtrying to see if Christine is staring daggers at me.
DR. BELSITO: I think what we have the most information on are the silicates/silica. I'd like to see that one
probably come first, then see that goes.
DR. SNYDER: From that old report. I think that's where we have the most data, that old report.
DR. HELDRETH: And doing them sequentially, we give the CIR Science and Support Committee time toevaluate the second group.
DR. BELSITO: Yeah, the second group.

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MS. BURNETT: This wouldn't come back at least until September anyway, just due to the meeting scheduling thisyear. I have no preference.
DR. LIEBLER: Okay. Well, I think one then the other makes sense.
MS. BURNETT: Probably silica first.
DR. LIEBLER: Yeah.
DR. BELSITO: Okay. So then that's what we're doing. So now can we go back to Women's Voices for the Earthletter and decide how we're responding to them?
DR. SNYDER: The 25th? Which one are we looking at first?
DR. BELSITO: April 8th is the date.
DR. LORETZ: There's two. I dated the Wave 3 as today. Their submission came in on the 25th of March.
DR. BELSITO: There are so many handouts here.
DR. LORETZ: I think you had it.
DR. BELSITO: I've got it. So the first is about crystalline and amorphous silica. Crystalline silica is on Prop 65,
amorphous is not. How are we addressing that, by saying we're looking at the respiratory issue?
DR. LIEBLER: I think this letter, at least the whole first page and much of the second page, is about the issue ofreporting the presence of crystalline silica. And I'm not familiar with how the California Safe Cosmetics database
works, but basically, what Ms. Scranton is pointing out is that they're only required on that database to reportingredients that are on the Proposition 65 carcinogen list, which includes crystalline silica but not amorphous silica.
So the products containing amorphous silica aren't on there. And the ones that contain or may contain crystalline
silica are. And she then lists on the next page a number of producers and cosmetics companies that have reported
presence of crystalline silica in the state’s Safe Cosmetics Program database.
Did I paraphrase that correctly?
DR. BELSITO: Yeah.
DR. LIEBLER: Okay. The next issue is particle size, we come back to that; but the presence of crystalline silica is
obviously some -- is of concern.
DR. LORETZ: I wish Jay were here. I totally forgot about that issue, because he was the one who looked into it.
And I think some of that is in error. So I think we looked at that and didn't agree with what they were saying; thatsome of those reports, in fact, were not what Women's Voices for the Earth mistakenly thought they were.
DR. LIEBLER: Okay. I mean, when we see this report again -- so I think it probably should be noted at this
discussion in the minutes that this was discussed and acknowledged, and that we agreed that there was apparently
some -- potentially some conflict between what Ms. Scranton is reporting to us and what the council has determined,
and we need to reconcile that for the next look at this report.
DR. BELSITO: Let me clarify. So what she's saying, companies reporting to California that they containcrystalline silica, that may be inaccurate?
DR. LORETZ: I believe so.

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DR. BELSITO: I sort of do, too, because I know -- for instance, if a product contains tar, it has to have acarcinogenic label in California. Neutrogena does not sell their T/Gel shampoo in California, because they would
have to label it. They do sell T/Sal, which has no tar in it.
So they're one company who won't label for California and just will restrict sale of products in that state. So I'm
surprised to see them on the list as a company that would do that, since their practice, at least up until now, has notbeen to label for Prop 65.
DR. LIEBLER: So let's just hypothetically say that the council is able to resolve this list down to one company thatreports this; what do we do then? If there are one or two or five instead of whatever?
DR. BELSITO: Well, it doesn't really matter, because it begs the question as to whether they're using crystalline
silica, as opposed to amorphous. And it begs the question as to whether we agree with the State of California thatit's carcinogenic.
MR. JURD: California actually does define it also as respirable. It's not just crystalline. They actually go further
in defining, in the Prop 65 list, that it is respirable.
DR. BELSITO: Okay.
DR. LIEBLER: Respirable crystalline silica, not just crystalline silica.
MR. JURD: Not just crystalline silica, yes.
DR. LIEBLER: Okay, but not referring to respirable amorphous.
MR. JURD: Not respirable amorphous.
DR. SNYDER: Okay. We have to get some of this clarified. And I think, as Dan said, Jay sounds like he's on it.
So we just want to make sure that he reads the minutes of our concern, and addresses the issues, and brings someclarity to that.
DR. LORETZ: Yes. We'll bring that one back, definitely.
MR. JURD: There was discussion this morning at the other panel meeting, also, on the same point. And I thinkthey were mistaken. There was a mention that maybe we're looking at Ti02 and not -DR. LORETZ: Yeah. That's exactly what I remember, that it turned out it was actually Ti02 that they were talking
about. But I didn't want to say that because I'm not clear on the details.
MR. JURD: Yeah, I think that's what it was. I'm not clear on the details, but that's what they mentioned maybe in
the source -DR. SNYDER: What’s Ti02?
DR. BELSITO: Titanium dioxide.
DR. SNYDER: Okay.
DR. LIEBLER: Which is really low (inaudible).

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DR. HELDRETH: So from the standpoint of this letter, it came in later than the publication of the report, andpretty late to even make it into our Wave 2. Since this is going to come back to the panel, likely in September, this
could be incorporated as part of the report package.
DR. LIEBLER: Sure.
DR. HELDRETH: And the panel will have time to fully consider this more. We'll have Council’s input on it by
then. And I can write to Ms. Scranton letting her know the panel has seen it, they want to evaluate it in full detail,see you in September.
DR. LIEBLER: Next time this is reviewed.
DR. BELSITO: Okay. So there will be no detailed specific response, rather than simply saying, thank you, it'sunder consideration. The panel will be looking at this as well as other information that we've requested. You cansee our discussion and our document online.
DR. HELDRETH: Once the panel reviews it -DR. BELSITO: Right.
DR. HELDRETH: -- then we'll get back to you again.
DR. BELSITO: Okay. I'm fine with that response. Anything else on silicates? So splitting them, but the dataneeds remain the same for both groups. And our recommendation is to come back with silica/silicates first, but
we're open to trying to tackle all of them at the same meeting as well. If there's some thought that the data will help
cross the boundaries, help us out.
Marks’ Team Meeting – April 8, 2019
DR. MARKS: Okay. Any other comments about the fatty acids? Next is the silicates, and I’m going to refer to theinformation we found on our desks this morning as Wave 3. And there’s some pretty significant issues. There’s amemo from the CIR Science and Support Committee, and then Christina also sent us a memo about silicon silicates.
So Tom and Ron, perhaps you first want to read those? And then when you’re done reading those, we can open thediscussion. Tom and Ron, have you had enough time?
DR. SLAGA: I’m still reading, but you can proceed if you’d like.
DR. MARKS: No, I think that letter is important, so continue to read.
DR. HILL: In the next two minutes I should be done.
DR. MARKS: Sure. So Christina, I think it’s going to be interesting. We may need Bart to help clear up thechemistry of all this, but we’ll see where we go. So this is a draft tentative amended safety assessment of silica andsilicate ingredients. At the December 2018 meeting, the panel issued an insufficient data announcement for the 40
silica and silicate ingredients. The additional data were a range of particle size, particularly in sprays and powder
formation.
We have comments about the importance of particles in these communications since this meeting. The chemical
characterization, except for silica -- and that’s also been a question of what really are the composition of this groupof ingredients, and are they really similar enough to group together in method of manufacture for the ingredients?
Our team thought that, in December, we could issue a conclusion of formulate to be non-irritating and assess the
respiratory concerns at discussion. But since then, we’ve gotten a letter in Wave 2 from the SASSI, which is theSynthetic Amorphous Silica and Silicate Industry, concerning SAS, which is synthetic amorphous silica, discussing
the inhalation and chemistry.

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And then today, we’ve gotten information from the Personal Care Products Science and Safety Support Committee
for the CIR concerning the grouping and concerns that these are not structurally related and about the composition in
ingredients and, particularly, a number of the ingredients that contain other components like germanium andzirconium and silver. And Ron Hill, you expressed concern about silver in the past.
So they suggest reconsidering a large number of silicate ingredients in this report because the ingredients are notsufficiently related structurally to form a useful ingredient family. And then their comment was the particle size inthe finished cosmetic product is not the same as the particle size in ingredients. So the lack of particle size should
not lead to an insufficient conclusion. The memo from Christina, date April the 8th, includes the Women’s Voicefor the Earth letter, and their first point related to confusion about the CA -- I assume that means California -- Safe
Cosmetics Database and the manufacturers who have reported the use of crystalline silica. And they recommend -MS. KOWCZ: We have -- Dr. Marks?
DR. EISENMANN: We have looked at that database over the last -DR. MARKS: Okay. Let me finish the letter, and then we can address all this. And then the second was theparticle size, again, of the ingredients are highly relevant. So I think they were the two main points from the letter.
Okay. So it’s gotten, perhaps, more complicated since the last meeting. Carol, Alex?
DR. EISENMANN: We looked at that data -- California’s database, and we believe the companies are reportingtitanium dioxide, not silica. Silica and titanium dioxide both have this non -- the same qualifier. And for somereason, when you search silica, these companies reporting titanium dioxide are coming up. The name silica, if it’sseen on a label, means a more synthetic amorphous silica. It’s not a crystalline silica. Under the name silica, they’re
not using crystalline silica, they’re using an amorphous silica.
DR. MARKS: And just for general public importance, what is the significance of the difference, in terms of
toxicology and safety?
DR. EISENMANN: Crystalline silica, when it’s taken up by -- as I understand it, when it’s taken up by
microphages, it causes them to burst and then results in adverse lung effects which leads to cancer. Whereas,
synthetic amorphous silica can be cleared from the lungs without causing any additional problems.
DR. MARKS: Okay. Good. That’s the way I interpret it, but I wanted to hear it from you. Okay. So I think that
addresses the California issue with the Women’s Voice of the Earth point.
DR. HILL: Can I just ask a follow up clarification question? So what she’s saying in here, if I understandcorrectly, is that there are companies that make lots of silica containing compounds, but they are only selectively
reporting. And what she’s asserting is that, presumably, because of the requirements of Proposition 5 -- or excuse
me, 65, which would relate to carcinogenic potential, that they’re reporting specific ones because they havesomething in there of concern. So what you’re saying is the products that they’re reporting all, without exception,
seem to have titanium dioxide and that the labeling -- or the reporting is based on that and not silica. And you can’ttell from the way the database is constructed?
DR. EISENMANN: Correct. When we looked at the database, we could only find that they were reportingtitanium dioxide and not silica. Because the silica they’re using -- if they’re using the name silica, it’s synthetic
amorphous silica.
DR. HILL: Okay. And then the other question I had in this document is related to what she’s addressing on the last
page, which is the jet milled powder issue. But then it finishes off with powder presses. And so then I thought whatin the cosmetic or personal care product would they be using powder press -- to press jet milled powder, except that
this is an article in the cosmetics and toiletries news -- some news publication from 2012.

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So that concerns me because if there are jet milled powders that are being included in powdered products, that could
be potentially inhaled with those particle sizes -- and I have a lack of clarity in terms of what those particles are like
and whether they present the same issues as crystalline silica. I’m guessing not because it would then be crystalline
product, which would be more along the lines of nuisance dust; but it would sure be nice to have confirmation ofthat.
In terms of your letter about the ingredient grouping, you’re preaching to a member of the proverbial choir because I
would like the ingredient groupings -- I understand the convenience of administratively grouping them, but I think it
occludes and obfuscates the ability to see clearly the issues that are there. And I just don’t understand -- other thanadministrative convenience and some similarity in the elements that are in there -- why you would group clays witha synthetic amorphous silica.
I would break out the different clays even, or at least make sure that they’re very clear in the subcategories. But I
didn’t have any problem with that because we already had a clay report a few years back, and I was fine with all of
that. But putting it together with silica just didn’t sit well with me.
DR. EISENMANN: And if you don’t separate in different reports, at least within the report, it’d be helpful to havethem separate, rather than one paragraph that has silica and clay in one sentence. And then the next sentence is -and you don’t know which -- do you support which ingredient.
DR. HILL: Within the body of the report, you can segregate the information, and that’s fine. But then the problem
comes when you get cumbersome conclusions where you have to split out conclusions based on large differences in
the ingredients. And I think when you have ingredients that don’t belong together based on how you would arrive at
the conclusion -- and maybe I’m not thinking thoroughly through this enough -- then, to me, that’s a good enoughreason to split them out. But that’s just my take on this, in reading all the information here.
DR. MARKS: So Ron, you would reconsider the numbers and split it out. Tom, how do you feel about that, too?
DR. SLAGA: There’s no doubt that they have a good point, and the groupings are different. As Ron said, theelements are the same, but there is structural difference. Are we saying, now, to have these two groups within one
report? Because I think we can come up with the same conclusion, can’t we?
DR. MARKS: I would think so. The last time -- and again, Ron Hill, you probably have the exception. Our team
was actually ready to move on and say safe when formulated to be non-irritating but address the respiratory
concerns in a discussion, as I recall in the minutes. In the last meeting, the Belsito team really had the concerns
about the inhalation, and that’s why the insufficient.
So I guess one way to address the different ingredients is to acknowledge that they’re structurally different throughthe groupings. And the two groupings you’re talking about now -- you said silicas and clays. Is that what we meanin terms of the chemical groupings? Because Bart -- I’m sure Christina was the one who put this all together. I wish
Bart was here so he could -- but maybe, Monice, you could comment.
DR. HILL: Well, let me just dispute what you said about the elements are the same because, in silica, there issilicon. There is oxygen, nothing else. But the clays typically have iron, other elements that are in there besides
silicon and oxygen and nothing else.
DR. MARKS: Is that where the zirconium, the silver and all that -DR. HILL: Yeah. So then you get other metals. And the ones I raised, I wasn’t necessarily sure that there was any
problem, but we were lacking data to cross read to the things that are more exceptional, like silver and gold,
germanium -- there was one other -- zirconium.
DR. MARKS: Yeah. Zirconium was mentioned.

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DR. HILL: I wasn’t as concerned about zirconium because I think that’s fairly pervasively occurring in some kindsof clays and such. But I think, when you get into some of these ones that have -- they’re higher atomic weight andhave different redox properties than some of the other elements, then that’s different.
DR. MARKS: And then, to be consistent, when we say silica, we’re talking about synthetic amorphous silica.
Yeah. And that’ll have to be very clear in the document that that’s what we’re talking about.
DR. HILL: And that was interesting because the 2004 SIDs that’s referenced includes synthetic amorphous silica
but also silicic acid, which again, is oxygen and silica, calcium salt. So there is calcium besides the oxygen andsilica, and salicylic acid, aluminum and sodium salt, that’s also apparently in that same report. I’m not sure why
they grouped that in there, as well, but there must have been a reason. I didn’t go back and research that because it
didn’t jump out in my mind until this.
DR. EISENMANN: They considered the solubilities similar. That’s low water solubility is why they can groupthem together.
DR. HILL: I see.
DR. MARKS: Monice?
MS. FIUME: First, I’d just like to respond to one of the paragraphs in the comments that were received today
regarding groupings. Yes, often when we group ingredients, it is for read across, but that is not the only reason that
we create groupings.
If a family seems to belong together for several different reasons, they can go into a report. When we do ourbotanicals, they’re grouped because they’re all the same genus species, but they don’t necessarily support eachother. So I did want to clarify that read across is not the only reason to group ingredients. But I do understand theconcerns about these being different.
In the past, Christina can definitely go through and break out the clays versus the silicates to make it easier for you
to read. We’ve done this several times in the past, especially when the information in the report is leading to asimilar conclusion. If the conclusion is going to be safe for all of the ingredients, we can explain that in thediscussion how the different aspects in the report came to the same conclusion, even though what we’re looking at
might not chemically be specifically the same.
Dr. Hill, I know you said you don’t have a problem with the zirconium, but the zirconium being raised -- that
ingredient was reviewed before. So somehow or another, it has to be addressed because this is a rereview of a reportthat had the zirconium ingredient in that 2003 report. So that can’t really come out. It has to be addressed, but wedefinitely can break down the groupings.
We can have a mixed conclusion if some of the ingredients that are in there are not considered safe, but the others
are. We’ve done mixed conclusions. And we have done reports where we have split them by different families andbrought you all the information, and then bring it all back together in the discussion as to how the conclusions werereached.
DR. HILL: But we’ve also split out into separate reports when we thought there was good reason to do that, and I
don’t really understand what the big difficulty is with creating three different reports, as opposed to trying to geteverything properly grouped within one report. And when I came on the panel, the idea behind groupings was that
we would be using that for read across; and they should be no brainer read acrosses or we wouldn’t put them
together in one report. So we’ve certainly departed from that quite a way.
Botanicals are different. I don’t think we should even think about botanicals in the same way as we think aboutother classes of agents, such as silicas, such as polymers, such as like that. Even some of the polymer groupings

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have been very cumbersome in terms of putting them together all in one report, but at least -- I think, from aphysicochemical properties point of view, it makes sense.
So I mean, it’s not up to me. But if it were up to me, there would be probably two, and maybe three, separate
reports here. And I realize we may leave some strays that have, again, silver, gold -- some of these other elements
well and good. If they’re not in use, then strays are just strays. If they are in use or we’ve reviewed them before,
like zirconium -- which I think was one of the reasons it was sticking out in my mind, and you just put words to it.
No problem there. But to me, that would group with clays and not with silica.
MS. FIUME: Again, it’s always a prerogative of the panel. That’s why we bring the rereview groupings to you to
be approved. With the rereview, you do have the option to change your mind. But having the whole panel weigh inon it would be great. And as I said, we have done it where it’s separate reports; but generally, in the past, we’ve
broken them out into different groupings by different families and kept it within the same document.
DR. SLAGA: So we’re going to table it until -DR. HILL: We’re not deciding anything today.
DR. MARKS: Let’s -- before we get to what I will move tomorrow, I just want to clarify. I’ve heard two groups
and I’ve heard three groups. So again, we’ll need direction for Christina what our team feels. So Ron, you said twoor three? I initially heard the two groups being silica, which is synthetic amorphous silica, and then clays. Is there
another one you would put in there, besides those two?
DR. HILL: If we were going to split our reports, then a starting point for me would probably be -- although, I haveto revisit this -- would probably be silica, and we could decide if there are a couple of others -- again, if it’s justsilica and oxygen, we can put silicic acid -- those things in there. I think calcium soluble silica still should be fine,
but that and everything else -- if we’re going to keep them in the same report, then I don’t think groupings -- they’remajor groupings.
And we can decide, then, how within the report to group. But the fundamental issue is, does it all stay in one report,
or do we create a separate report? What was in the silica report, again? There were two that we reopened. There
was one that was silicas.
MS. BURNETT: The original silica report contained silica, alumina magnesium metasilicate, aluminum calcium
sodium silicate, aluminum iron silicates, hydrated silica, and sodium potassium aluminum silicate.
DR. HILL: All right. And so the question would be those ones -- for example, the one with the iron in it, does thatstay there or go with the clays? I’m not willing to make an off the cuff comment on that one without looking again.
DR. MARKS: Okay. Carol, Alex, how do you like the idea of having the same report and just groupings within it?
I mean, we’ve done that, not just with the botanicals. I think we’ve done that with other groups of ingredients. Do
you see a problem from your point of view?
MS. KOWCZ: I think the one thing that we are trying to address with Monice is, if we are going to have one
report, then we do have to have specific delineations or differentiations of this chemical class versus that chemicalclass, because it is different based on the physical chemical properties, as Ron has stated as well.
So if we can do that with a mixed conclusion, as you’ve said you’ve done in the past, we just feel that they’re very
different materials and that they should not be all grouped together. But if that’s an opportunity to do it in one
report, with different conclusions and really showing that the data goes to which group, I think we’d be fine withthat.

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MS. FIUME: And I guess the reason I was pushing for the one report with the subgroupings, is because that 2003
report that initiated the rereview does have a mix. For example, kaolin is in that 2003 report, as well as the silicates.
So it is very mixed.
So it seems, in order to take that rereview forward of that report -- if we could create subgroupings in this rereview
document and, therefore, address the ingredients that were looked at in 2003, that would keep the family from the2003 report in the same rereview, but also explain the different groupings that were included originally and how
they’re being looked at now.
DR. HILL: So if it were up to me -- if I ran the zoo, we would create new reports. And one would be silicas, andone would be clays, and one would be zeolite and maybe a diatomaceous earth; and one would be other things, thataren’t silica, that aren’t clay, that aren’t zeolite, that aren’t diatomaceous earth.
And I’m thinking, in terms of zeolite and how I know those are used industrially, I think it’s interesting they end up
in cosmetic ingredients. So we would have strays, but I’m pretty sure I would create four reports, maybe five, if I
ran the zoo. And I don’t. And they would be new reports, and then that would give the opportunity -- because I
think there are still some issues out there in the wind, no pun intended, but maybe about aerosol sprays, for example.
Because again, I think we’re still missing -- and we identified them as we were trying to put to bed the aerosol
report, which I still don’t think we’ve ever -- our guidance document -- I don’t think we’ve finalized that, have we?
And promulgated it. But there were some pieces of issue out there, such as if you have an aerosol spray and then thesolvent evaporates as they’re flying through the air, and you start with the glomerates, depending on what thesubstance is in there -- what happens between there and it gets to my nose?
So it would provide a little bit of time, as well, to make sure we’ve revisited each of those as relates to the specificcategories of ingredients. Because when you’re mixing things like the flow chart -- that’s very nice that they gave
us. It’s fairly near the end of the PDF here that was from the SASSI -- shows with the synthetic amorphous silica
and how that relates to the others that are silicates. And there’s nothing else in there by silicon.
Those things all grouped together -- and then you could add, again, things that are only silica and oxygen, maybe acalcium salt, and then decide from there do we include aluminum-containing compounds or does that go in adifferent report. But I’m just looking at, if the issues are necessarily the same, can you discuss them all in the same
report? I’m sure you can find a way to do that.
But having to keep the same ingredients together in a rereview, to me, seems to be artificial. There’s no goodscientific logic. I wasn’t around when the 2003 report was put together and the grouping was established, so I don’tknow why I should be stuck with it, I guess, is one way of saying it.
MS. KOWCZ: Would it be difficult to separate them now with the 2003 report already established?
MS. FIUME: It can be done, and we’ve had ingredients that have been pulled out. I can’t speak to any of thechemistry as to why Bart put this together. So I would really rather let Bart comment on his feelings on keeping
them in one report versus separate, because he builds the documents based on his chemical knowledge. So I would
prefer to let him comment on it, if that’s okay.
DR. MARKS: Sure. Tom, what’s your feeling about this? You proposed tabling it, but I’d like to get back to thediscussion. Perhaps, we know where Ron Hill stands with having multiple reports. You had previously -- and I’mcertainly fine with having one report. We do many reports where we have split conclusions. So I think Bart’s input
is going to be very important.
I kind of like the idea of tabling it because I think we’ve gotten enough new information. In terms of particularly
handling the structure, I don’t know how we can move forward with a tentative amended report if we don’t have it
clarified as far as what are we going to do with these different structurally chemically different ingredients and how
we’re going to group them.

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And I actually kind of liked, Ron Hill, your approach. You have the silica. you have the clays, and then you could
have an “other” group or a “miscellaneous” group, and still have it all in the same report. I guess then it’d be up to
Bart to name what that miscellaneous new report would be.
Whereas -- would the title of this still be silica and silicate ingredients, or would it be silica and clay ingredients? Or
would the title change now since we’re -- so that’s another thing to think about, because it doesn’t sound like silica
and silicate ingredients really cover these structurally different ingredients.
DR. HILL: And honestly, when I read the SASSI -- the most recent input, I thought, okay, they have some thingsin process currently, as well, related to all of this. And that if we were able to table and have just a little bit of space
and time to think about how better -- it could come back as quickly as June, perhaps, if we get information from theindustry group. But I was around for 2008 when we got that first -- I was here in 2009 when we were still looking at
the SASSI input data, and I remember we had at least one of those individuals from that organization come and give
us a presentation, if I’m not mistaken.
So I just felt like my take on reading that was could we table this and have a look at those issues seriously; discusswith the industry groups, and decide what this should look like in the end? And the other thing I was going tomention while I’ve got the mic -- and then I’m going to shut up and shut it down -- is there any chance we can get
Bart in for this discussion? Can we table for the moment and sometime between now and the end of the afternoon,
if we’re the ones that have to move tomorrow, get Bart in for some of the discussion? Or do we have that all happen
overnight?
DR. MARKS: I feel comfortable moving tomorrow table, and raise the reason that we feel we table it because we
had a structural ingredients difference. The issues have been raised by the Science and Support Committee andactually also -- now, I guess it wasn’t raised by the Women’s Voice of the Earth. They will remain particle size.
DR. HILL: I wanted clarification about this jet milling thing, because I think we’re still okay just because it’s not
crystalline at that point. But I wanted to feel a little better about that.
MS. KOWCZ: Dr. Marks, can we just ask -- we have a representative from SASSI -- because this is the perfectopportunity to ask any questions. And we do have the industry expert.
DR. MARKS: Excellent. So would you please introduce yourself, and you can use SASSI but also tell us what thatmeans -- meaning the full name of it. I know what it is here -- the Synthetic Amorphous Silica and Silicate Industry.
But for those of us who may not be within that industry, SASSI doesn’t mean a lot. It could have other meanings, if
you’re sassy.
MR. JURD: Brett Jurd. I am currently the chairperson of SASSI, which is a trade association actually formed in -about 20 years ago to differentiate synthetic amorphous silica from crystalline silica because it was, at that time,
being lumped together.
We are and work with a similar associate that’s part of CEFIC in Europe, called ASASP. The organizations havevery close memberships. We represent, basically, the eight to ten major synthetic amorphous silica producers
globally. We’re missing one or two companies there, but for the most part of -- all the major companies, PQ, PPG,
are all members of our association.
We do a number of things, including supporting studies. If you know it or not, there’s a lot of activity going on in
Europe right now. We would be more than willing to provide whatever support you need to come to the correctconclusion. A lot of our members also are involved in other silicates; you know, manufacturing, the ones that you
said were in the initial report.

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And we also, for one reason or another, the companies -- and I actually am with W.R. Grace. We actually do mineclays and also put on the market zeolites, although not for cosmetic purposes. But we have chemistry experts,
within our organizations, that can help differentiate those kinds of materials.
The one thing we feel very strongly about with synthetic amorphous silica -- and I think the points made earlier
about the differentiation between the crystalline form, which is classified as carcinogenic, particularly the respirable,
the less than ten-micron particle size, and synthetic, is there’s a significant health difference between the crystalline.
Even California differentiates crystalline amorphous respirable silica as the carcinogenic version, not just larger
particle sizes.
DR. MARKS: I don’t know whether you want to -- since you’re here and you may add -- we had a rather robust
discussion prior to you coming into the room about the structurally different ingredients, which are grouped together
in this tentative report. And that was also raised by the association manager in a letter -- that clarification on thescope of the 40 ingredients. And this was authored by David Pavlich?
MR. JURD: Yes.
DR. MARKS: So I guess what our team is struggling with, or discussing, is whether to have one report dividing
these ingredients into two or three groups, a silica group, a clay group, and another group, which would be amiscellaneous group of ingredients in the same report, versus having multiple reports. This was also pointed out by
the CIR Science and Support Committee of the PCPC. What’s your feelings about splitting it out and how you
would do that? One might be the report just on silica, which we now -- when I say silica, I refer to synthetic
amorphous silica, SAS.
MR. JURD: We would agree. We would like separate reports. Particularly, as was mentioned, I think clays fit
into a different class. There can be a lot of contaminants -- other materials in clay, including crystalline silica. So
you’ve got that component that could potentially be in there and could be an inhalation hazard in certain types offormulations in cosmetic products. That’s an opinion on my part not supported by any scientific evidence.
I think you would have to look at maybe -- like zeolites, you could do an aluminum silicate or alumina silicate kindof grouping. A synthetic amorphous silica, which I think is the majority of the silica, if not all the silica that’s foundin cosmetic products, I think is chemical synthesized rather than naturally occurring. And then, as you mentioned, amiscellaneous, because there were some very unusual materials kind of lumped in that category.
And I think if you look at -- at the very high level, it’s like where else could they fit? Ah, this makes sense. We canlump them in to here. But if you look at the data that’s out there -- and I think you talked a little bit about readacross -- I’m not sure if you could do read acrosses at this point in time because I don’t think the data is necessarily
there to be able to afford that conclusion.
DR. MARKS: Okay. That helps us -- reinforces that we need to have different groups. I think the question will bedo these different groups occur in the same report, or do we split it out as different reports? And we’ll handle that in
the future. So tomorrow, I’m going to move that we table this because of the ingredients that are structurally
different, and I’ll kind of summarize what we talked about, Tom and Ron. And obviously, feel free to add into that.
Any other comments from our -DR. SADRIEH: I’d like to just mention that, regardless of what’s done in the end, I’d like for the issue ofmagnesium calcium silicate to be addressed, which is asbestos. So that’s something that -- whatever conclusion you
come to, I think the potential for any kind of asbestos contamination would have to be addressed.
MS. BURNETT: Did you say magnesium calcium silicate is not an ingredient in this report?
DR. SADRIEH: Correct. But you could have contamination. Asbestos contamination is not an ingredient. You’relooking at ingredients.

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DR. MARKS: Yes. That obviously gets to the impurities portion of these ingredients. So just as we’ve heard thatclays may have crystalline silica as a contaminant in it or a component impurity, so the same way we’d have to deal
with asbestos, too. Thanks for bringing up that point. Yes?
MS. BURNETT: Before we move on, in the Wave 2, I asked -- I know there was a lot of data points. How would
you like to have that data represented in the report, if at all? It was SASSI provided different particle size readouts
for different samples of -- I think some of them were cosmetic products. Some of them were straight.
DR. HILL: Excuse me. It came to my comment about making sure that we revisit our inhalation/aerosols
document and where we landed two meetings ago. I think we looked at some of that in December, didn’t we?
MS. FIUME: Right, it had not reached finalization yet.
DR. HILL: Because I don’t think there’s any really new information. They sent us a data dump is what it appeared
to be, with some particle size characterizations, which is helpful. But I don’t know that there’s any new informationin there whatsoever. I think where I still have data gaps is -- we had a pretty good summary, and I think a lot of it
came in that SASSI report from 2000 -- S-A-S-S-I report from 2008 about the issue of agglomeration in finishedcosmetic products.
But once a manufacturer of an ingredient sends it to the formulators, then it’s really on the formulators to figure out
what happens from there and if I spray it in an aerosol spray -- and now we have different aerosol devices. So thatwas something else that came to the floor in that last round -- the last rounds of data we had is that, well, there’s notjust one kind of aerosol can and one kind of pump spray.
There are these other things that we hadn’t maybe fully considered. And any given ingredient, I’m not sure we havethe full scope of everything, but we’re supposed to be getting it and reviewing based on what information we do get,what kinds of devices do we have? Are they for sure larger particulate agglomerations? Because the particle sizes
that I gave us are, I think, are the raw ingredient before it ever goes into a product, if I’m not mistaken, in that Wave
2 data dump that we got. So that doesn’t really give us the full picture because -- unless that was added to a facepowder.
They talked about the feel of these jet milled powders, and that’s what got my attention; is what’s added and what’s
actually being sold to the consumer, and what particle sizes are in there. And is there anything crystalline as animpurity is the immediate concern. And beyond that, is it nuisance dust or something else we have to worry about?
And we have these inhalation documents. We’ve got these face powder and loose powder, and then we have somestatement about exposures are thus and such related to workplace exposure. And I’m thinking, well, yes, but what’s
the stuff? If it’s just nuisance dust and it’s innocuous, and we don’t have to worry about anything that might happen-- sensitization in the bronchials, for example, or something like that -- that’s one thing.
But there’s disconnect every time I read that statement right now. And we talked about that as our -- not boilerplate,that’s the wrong -- our guidance document is being updated. That we had these issues that were still out there. I
don’t know if we could ever actually resolve them because the science keeps improving in terms of what we know.
But the other thing that came to the floor is it actually assessing how much of what size of particles come into
somebody’s breathing zone and what the actual exposure is daggone hard, if not almost totally impossible.
I just know if my wife’s using hairspray in the bathroom -- where she hasn’t much used aerosol sprays anymore.
But if she is, I can’t walk in there because I’m going to be coughing for the next ten minutes. That’s a sentinel.
That’s my defense mechanism. I don’t worry about any danger to me, but it doesn’t take much to trigger that coughreflex. So I know there’s particles, and I’m breathing them.
MR. GERMILLION: This is reminding me. There was a discussion at the last meeting, or two meetings ago,
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DR. MARKS: Yeah. That’s correct. Ultimately, it turned out to be issuing this insufficient data announcement
and asking for the particle size. But you’re absolutely right. Our team felt that we could handle the issue withinhalation in the discussion and not put that in the conclusion, but we lit on doing the insufficient data
announcement.
Now, we have gotten more data. Obviously, synthetic amorphous silica is not an issue with inhalation. It’s not a
respiratory toxin. And then we have this memo from the CIR Science and Support Committee. And basically, inreferring to particle size, the finished product -- cosmetic product is not the same as the particle size of theingredients.
So it’s the end product which we should be, again, addressing, and that needs to be addressed in the discussion, I
think. So the lack of ingredient particle size should not lead to an insufficient data conclusion. I don’t know if thatanswers your question, but you’re absolutely right. Actually, that was one of the big discussant points last time.
Not so much the structural differences among these different ingredients, which we’ve lit on in this meeting, but theprevious one was really the respiratory issue.
MR. GERMILLION: Yeah. And I remember that back and forth, and then I’m looking at this Women’s Voice for
the Earth letter. And she starts another reference to particle size and the manufacturer representing particle size atsome level.
DR. MARKS: So I think we will address that in this. We’re going to have another crack at this, if not multiple
cracks at it or reviews. Because if indeed we table it tomorrow -- and that’s what our team will move -- then not
only will we deal with the issue of structurally different ingredients, whether it’s in the same report or multiple
reports, but we’ll also, I’m sure, go back and address the inhalation toxicity. And for SAS, that does not seem to be
an issue. It’s going to be these others, perhaps, and particularly the clays where you could have contamination withcrystalline silica and asbestos, too, if that’s an impurity.
DR. SLAGA: All the data in Wave 2 on particle distribution could be summarized in the report. I don’t think weneed all -- Ron should be able to help with that.
DR. MARKS: Well, and Ron Shank did.
DR. HILL: And it strikes me in listening to this -- we have language, for example, formulators should take caution
not to put a penetration enhancer in the same formula when dermal absorption was our index of safety or lack ofdermal absorption was our index of safety.
And I think we need -- and it will probably depend on the exact ingredient and situation -- comparable language herethat it shouldn’t be formulated to set up this scenario, which potentially sets a risk. And that could probably even
include crystalline silica, provided it’s in some cream where there’s zero chance that it will ever be volatilized
versus an aerosol can where perhaps we’re not quite sure in some cases.
DR. MARKS: Robust discussion. Any other comments? So Tom and Ron, I’m going to move that we table these
ingredients tomorrow. We’ll, I’m sure, in the discussion tomorrow decide whether or not we’re going to move
forward; for the time being, at least it’s a single report with split out ingredients within that or multiple reports. And
I suspect we will touch on inhalation again, perhaps. Certainly, that’ll come up again multiple times. Thank you foryour comments.
Full Panel Meeting – April 9, 2019
DR. MARKS: So in December’s meeting, the panel issued an insufficient data announcement for the 40 silica andsilicate ingredients. The needs were listed in Christina's March 15th memo, particle size, chemical characterization,
method of manufacturing.

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Since that, particularly in Wave 2 data, we received a letter from the Synthetic Amorphous Silica and Silicate
Industry (SASSI) concerning synthetic amorphous silica (SAS). And that that wasn't anywhere near the same as
crystalline silica, didn't have the toxicity of crystalline silica.
And then also, in Wave 3, as I’ll refer to what we received yesterday, was Women's Voices for the Earth letter, andthe CIR Science and Support Committee letters, all concerned about the grouping of these different ingredients, andthat they were dissimilar.
So, that elicited a significant amount of discussion on our team. We move that these ingredients be tabled and be
represented to us. And what we suggested, we weren't sure whether it be three separate reports or in one report.
Personally, I was fine with one report. But the groups would be the silica group, which is the synthetic amorphoussilica, clays, which may have contamination with crystalline silica, and then other ingredients, such as that containsilver zirconium. And look at these different groups separately.
So our motion is to table it and relook at this once these have been divided up by structural groups.
DR. BERGFELD: Is there a second, or a discussion or a comment?
DR. BELSITO: Well, I don't know if we said table or not, but we agree with splitting the report into silica andsilicates from all the others, and then trying to look at all the others separately but start with silica and silicates. And
our data needs haven't changed, method of manufacture and impurities, and particle size in materials that are used in
powders and sprays.
So I guess if that's a table, then it's a table. But I think of a table as the report just staying as it is, and that's not what
we're requesting. We’re requesting that it actually be split, for now, into two, that silica/silicates be a separate reportaddressed first.
DR. BERGFELD: Bart, you want to comment on that?
DR. HELDRETH: Either process is possible for the panel to take. I think if we're not waiting for some new data,or some new information to come in, then it does make sense to proceed and not put it in a table mode where we
don't know where it's coming back.
Also, yesterday, I heard from the Belsito team that we would do these sequentially. And do the silica and silicates -immediately return as a new report in the process, whereas the rest would constitute another report. And this would
give us time to focus on the silica and silicates, and also give industry time to take a look at that grouping and let us
know their thoughts on those materials.
DR. BERGFELD: So it sounds like this is just an administrative movement that we do not have to go out as
insufficient, we don't have to table, but we will take it as a tentative -- a draft amended?
DR. BELSITO: It’s still insufficient, though.
DR. BERGFELD: Yeah.
DR. BELSITO: Because we still want method of manufacture, impurities, and particle size for use in powders andsprays. So there are data requests that are there.
DR. BERGFELD: So, do we send this out again, as an insufficient data request?
DR. MARKS: I guess one could send it out as a revised draft tentative amended safety, because that's what we're
doing, really revising it, and that would be the next iteration.

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Just to go back to particle size, both from the manufacture SASSI, the industry, association of manufacturers, andthen also from the Science and Support Committee, they address the particle size. And from the Science andSupport Committee, particle size as finished cosmetic products are not the same as a particle size of the ingredients.
The lack of ingredient particle size should not lead to an insufficient data conclusion.
So I don't know whether industry wants to address that; but if we send out an insufficient for particle size, I guess
we're ignoring what the Science and Support Committee has responded to that request.
DR. BERGFELD: Alex, you want to respond?
DR. BELSITO: I’ll let Paul respond, but I mean, I don't think we have to agree with what the committee says. We
didn’t yesterday.
DR. MARKS: On, no. I agree. I just think we need to rationalize, you know, why we're stillsaying --DR. SNYDER: I think we were taking an ultraconservative approach because there is a risk if these are inhaled,because it will cause a hazard. And so we want to fully understand the particle size distribution and have better
appreciation for that before we approve. And so I think it’s a high-level approach. We'll ask for the data and thenonce we see their justification for needing or not, then we can make our final conclusion at that appropriate stage.
DR. MARKS: Paul, would it be -- I'm kind of just thinking out aloud here -- would it be similar to the monomers?
And when we look at those ingredients, how much free monomer is left? How much free of the small particle size?
Because it seems like what we're getting is that these aggregate in the finished product; so therefore, whatever westart as a particle sizes is irrelevant. Unless, to my mind, there are residual small particles, I guess. Is that reasoning
correct?
DR. SNYDER: That’s correct. And we were assured that once they've aggregated or agglomerated, whatever you
refer to it as, that it's nearly impossible for them to dissociate. But again, we don't have the data to know how muchof what impurity in regard to any smaller particles that might be in there.
DR. BERGFELD: Carol, do you wish to speak?
DR. EISENMANN: I still think there's a -- synthetic amorphous silica is so different -- and those two, the hydrated
silica -- and so different from the others, they can control the composition more carefully, if there is some solubility.
It's not an inhalation. If you inhale it, some of it will dissolve and get removed from the lungs, versus other silicates.
And I’d hate to see you keep putting those two ingredients, lumping them with the rest, because there is a big
difference between them.
DR. BELSITO: And I think we'll probably get a better understanding of that when we separate the silica andsilicates out. But it doesn't hurt to ask for now, and we may determine that it's not needed after looking at it.
DR. EISENMANN: And that's the information you've gotten in Wave 2, that they've already provided. And not
only that, there's an OECD summary, that the data is in the report, but within the report that hasn't come to the CIR
report yet, particle size and surface area is listed for a lot of the ingredients, that the data is in, that still has to be
added. So you have a lot of that already for SAS and the hydrated silica.
DR. BELSITO: Yeah, and we'll look at it. But I mean, I don't think we're prepared to withdraw ourrecommendations at this point for additional data needs. Again, when we look at it, we may determine that wereally didn't need these, as we often do.
DR. BERGFELD: I'm going to ask Bart to respond, because administratively we can handle this a number of ways.
So will you elucidate those or just explain the possibilities?

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DR. HELDRETH: Sure. I think that the possibility that seems most in line with the consensus that I'm hearing isthat we will bring back, at a future meeting, this draft tentative report, which will be revised. It won't be a newreport that's going to go out for public comment.
The silica and silicates draft tentative report will come back to the panel, and then there will be opportunity for thepanel to address the new report and the comment period will open thereafter.
DR. BERGFELD: So everyone understands, we -- just a minute, Ron -- we will not be voting on this. It's aconsensus opinion, that it will go back to the staff, divided up separate items -- or ingredient groupings -- and thencome back to us again for discussion and vote. Ron Hill.
DR. HILL: Actually, was not my concern that was discussed yesterday. But we asked about the implications ofremoving ingredients, given that this started as a re-review or reopen. And that's where we came and said, well,
does this need to be then a new report, or a series of new reports, number to be determined.
And I was only asking that question, because I was sitting here pondering what if the report that comes back is that
we only look at synthetic amorphous silica, which as we understand it, that's the only silica that should be used incosmetic products at this point; and then everything else, where we could keep silicates in with clays and so forth,because some of the issues in terms of safety would be the same.
And I just, I don't know if that's an option or not. How far can you cut down before it's not a new report, I guess iswhat I'm driving at.
DR. HELDRETH: I don't think anything is going to be left out here. All those ingredients that we've looked at
before are going to get reviewed. We're just reorganizing the format.
DR. HILL: But into one report, or are we breaking out into separate reports? Because that's what matters, I think,in terms of technicality of procedures.
DR. BERGFELD: It's my understanding that they'll first break it out into the different categories that we've
explained. And then the next meeting, we will decide how we're going to handle them.
DR. HILL: Okay, I wasn't clear on that, but got it.
DR. BERGFELD: Okay. Dan?
DR. LIEBLER: I want to clarify that the breakdown needs to include all the synthetics together. So, I don't know
if the synthetics are limited to hydrated silica and silica, or if there are any other ingredients on our current list thatare the synthetics.
But those are the ones where the composition and structure can be exclusively controlled. Many of our issues withpossible contamination with crystalline silica, or other things, that is already handled in the production of those.
So I just want to make sure that the grouping, the reorganization, puts those synthetics together, and doesn't
contaminate them, so to speak, with the mined or other silicas.
DR. HELDRETH: So then, to that point, which ingredients are those?
DR. LIEBLER: That is my question. And there's somebody here who knows, and it's not me.
DR. HILL: We got, at least -- and you weren't in this group yesterday -- Brett, from the SASSI, who also clearly
has expertise in many of these other areas and was aware that crystalline silica as an impurity in mined powders
could be a problem. Whereas synthetic, you're exactly right, when they can control what's there, then those issues
should go away.

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But then the question will be, I still think the silica grouping, whatever it is, should at least be restricted to things
that have silicon, oxygen, and maybe salts, thereof, calcium, aluminum, like that.
DR. HELDRETH: I don't disagree with that. But unfortunately, we don't know which ones are synthetic andwhich ones are not. For example, some of the salts that are listed in Table 1 would seem to be something that could
be made synthetically, but the definition says that they are mined.
DR. HILL: Yeah.
DR. HELDRETH: And the other ones, it's unclear of the source, or whether it’s -DR. HILL: So that's an insufficiency, really.
DR. BERGFELD: Well, I think that we can proceed and perhaps have some consultation with the CIR SSC
committee and see if we can figure this out.
DR. SADRIEH: I just wanted to mention that, you know, yesterday you brought up the issue of potentiallyevaluating as a contaminant, asbestos, which is magnesium calcium silicate. And so, I just wanted to make surethat, for the record, that it was mentioned right now.
DR. BERGFELD: Thank you. All right, I think we will move on then. Administratively we're taking this back,reorganizing it, and bringing it forth again, in the next meeting or so.

DECEMBER 2019 PANEL MEETING – GROUPING STRATEGY
Belsito’s Team – December 9, 2019
DR. BELSITO: Okay. So, we're going to the silicates and whether we were -- this is also in Admin, whether we're
happy with how things were broken down here. As you remember, there was the amorphous and now we're into themined. I guess the questions I had all were to Dan, and anyone else who can explain why calcium silicate is okay,
but calcium magnesium silicate got struck.
DR. LIEBLER: Yeah, that was the question I had.
DR. BELSITO: Sodium magnesium aluminum silicate got struck. It didn't really seem to me that these were so
different.
DR. LIEBLER: Yeah, I had the same question. I don't know.
MS. BURNETT: We can add them back in. It was just that they were suggested add-ons. And since the add-ons
kind of caused a quagmire, we thought, well these are no-brainers, so we pulled all of them out. But we can easily
add back in whatever ones you want added in.
DR. BELSITO: But how is lithium magnesium silicate a no-brainer, and calcium magnesium silicate is not a nobrainer?
MS. BURNETT: Those were reviewed originally. So, those were part of the re-review that we reopened, so they
already have a conclusion. So we still -DR. BELSITO: I understand. But if we're looking at them, and now we've all of a sudden gotten concerned about
inhalation, da, da, da, da, how is calcium -- I mean, I would be more concerned about lithium magnesium sulfate
silicate than I would about calcium magnesium silicate.

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DR. LIEBLER: So, these strike-outs are basically not because of some inside knowledge of chemical distinct
likelihood of being problems, but they're simply because they weren't previously reviewed, and we didn't want to
add them in?
MS. BURNETT: Yes.
DR. LIEBLER: Okay. I think that I -MS. BURNETT: If you want to keep them all in, we can.
DR. LIEBLER: Right. I agree. I think we can keep them all in, and I like the three-report strategy.
MS. BURNETT: Okay.
DR. BELSITO: Okay. So, you're happy with what's under silicates, Dan?
DR. LIEBLER: Yes sir.
DR. BELSITO: Okay.
MS. BURNETT: What about the clays -DR. BELSITO: Yes, private. What about clays?
DR. LIEBLER: Yes.
DR. BELSITO: Okay. And zeolites?
DR. EISENMANN: One comment on clays, is there’s an ingredient in the dictionary called clay that was 100 uses.
And there are also a bunch of site-specific clays that I think you should ignore. But the one ingredient that is called
clay -DR. LIEBLER: I think the issue before us right now is the three-report strategy or something else.
DR. EISENMANN: Okay.
DR. LIEBLER: So, I like the three-report strategy and if anybody doesn't, I'll see them out back.
DR. BELSITO: Oooh, okay.
DR. LIEBLER: But anyway, I mean, think that's fine. And then we can finesse the individual ingredients as we
get through these reports.
DR. BELSITO: Okay. Good.
MS. BURNETT: And keep all zeolites, then, too?
DR. BELSITO: Yeah.
DR. LIEBLER: Yeah.
DR. BELSITO: Okay.
DR. BERGFELD: I'm confused about the three-report strategy. You're going to have three more reports?

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DR. LIEBLER: Three different reports, instead of having all these grouped together. There will be a report on
silicates and a report on clays and a report on zeolites.
DR. BERGFELD: So, you're not accepting this?
DR. LIEBLER: That is what's proposed.
DR. BELSITO: We are. What we’re saying is, that they were striking out ingredients that had not been reviewed
and just keeping in those that were reviewed. And we're saying, no, if they're in the dictionary, let's put them all inand see where it falls, because Dan feels he can potentially read across. I mean, it's again, to get rid of calcium
magnesium silicate, and keep in lithium magnesium silicate, that would make no sense to me.
MS. FIUME: So, it’s just the difference of an add-on versus an existing ingredient?
DR. BELSITO: So, are we going to take these up all at one time then?
DR. BELSITO: Right. I understand. But it looks silly.
MS. FIUME: Yeah. Okay.
DR. SNYDER: Well, they're basically already written; they just got to par out the data, pretty much, right?
DR. BELSITO: Right. Yeah.
MS. BURNETT: I’ll do another search to make sure there is -DR. BELSITO: Right. Nothing new.
MS. FIUME: So, we're not going to approve this, we're just going to bring this back the three -DR. BELSITO: No, just before Christina wasted her time putting them together, are we happy with this way ofseparating them?
DR. KLAASSEN: Yes.
DR. BELSITO: We're saying we are. Okay.

Marks’ Team – December 9, 2019
DR. MARKS: Silicates. Let me see, where is that? Is that in the Admin too?
DR. PETERSON: Yep.
DR. HELDRETH: Yes, it is. PDF Page 61.
DR. MARKS: Oh, good. Thank you. I shouldn’t have gotten ahold of the admin folder so quickly. So that’s on
Page 61 of the admin folder.
And the big toxicity concern was inhalation silicosis, and that’s from mined silicates. So, the reason at the June
meeting this year -- Lisa, I don’t know how much of this you got from this memo in looking back.
But in June of this year, the Panel issued a final safety assessment of synthetically manufactured anamorphous silica
and hydrated silica are safe when formulated to be nonirritating. And we were reassured with that, that there was noevidence of inhalation toxicity by those two ingredients.

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And then we were going to have these other silicate ingredients included, but then it became evident that part ofthem, potentially, could be, mined. And then, now, we were in the inhalation toxicity issue. So, then, there was asuggestion that we divide these in three groups.
And I think also -- let’s see in your memo, Christina. Did it say constitute impurities -- so, first was, do you likethese three groups? And I guess, do we really need three separate safety assessments, or can we have one safetyassessment which has these three groups in it?
So, the first question is, do you like the three groups? I don’t think we have anything more than making anassessment. Do we like the groups?
DR. SLAGA: I like them, but I wouldn’t put them in one report.
DR. MARKS: Okay. Yeah, I think that’s important.
DR. SHANK: The three groups are fine with me. I leave that to the chemists. And if there are one report or three,
it doesn’t matter to me.
DR. MARKS: Lisa, you’re the chemist. Ron is now really putting you on the spot.
DR. PETERSON: Yeah, I thought that they were fine. The three groups were fine.
What I didn’t understand was why, like, zirconium silicate was included when it was no longer used; in that it’s
because there’s safety issues associated with that?
And then there’s one that was still in use, the -- I think it’s -- I’m still learning how to notate in the PDF file, but theammonium silver zinc aluminum silicate was still in use, so why was it crossed out?
MS. BURNETT: So, for our history, the ingredients that are not crossed out in those lists were already reviewed by
the Panel. So, back in June 2018, the re-review came up and we proposed these add-on ingredients, which are thered cross-outs. And we reopened the report to add all these ingredients in.
And then, through the process, we’ve determined that these reports weren’t as no-brainery as we usually go for addons, so we’re proposing to remove them. So, all the ingredients that are in black, without the strikeout, werereviewed in the same report and have the same safety conclusion.
DR. PETERSON: Okay.
MS. BURNETT: Now, the Panel does not have to remove those ingredients. If you feel that they all should be still
reviewed together, we can still go ahead with our review. Some of them may be closer in similarity than some ofthe others, but it’s up to you guys to determine whether they should be removed or added.
It just was our suggestion that, oh, maybe these weren’t no brainers after all. We still have to go forward with there-review process, because these are now hanging out there. So, it’s up to you.
DR. HELDRETH: Yeah, we used the frequency of use and concentration of use to inform us on which previously
unreviewed ingredients to pick and look at. But for those ingredients we’ve reviewed before, whether or not there’s
reported use for them is somewhat inconsequential when we’re doing a re-review, which is what we’re doing here.
The Panel’s looked at them before. It’s now been at least 15 years since the Panel’s looked at it, and it’s time to takeanother look at it and say, has the science changed? Has the concentration of use changed, the frequency of usechanged, and do we need to come up with a new conclusion or not?
So, that’s why those ones, like the zirconium silicate, that you pointed out, remain in our list here because they’redue for re-review, even though they may not be reported to be in use at this point.
DR. MARKS: So, instead of Freudian slip, Christina, in that last sentence right above the three groups of silicates,“CIR staff suggested that the remining ingredients be presented.” Because that was the big issue was, when we got
the composition at least, Lisa, the representatives from the amorphous silica industry -- SASSI, I think it was, sowhatever that is -- that they couldn’t tell us with a surety that these didn’t have mined silica in them, as part of theircomposition.
So, I think they have to be reopened just for that issue alone. It’s already reopened. But the ones that are in red andyou crossed out, if they’re similar ingredients, is there a reason not to include those from a -DR. HELDRETH: Those were proposed add-ons that we made.

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DR. MARKS: Yeah, now it says the remaining ingredients be presented in three separate reports. Yeah. Okay.
DR. HELDRETH: And so, we proposed taking them out just because it seems like it’s been so arduous to try tofinish these re-reviews. So, we’ve tried to simplify it, and take it down just to those ingredients that we really had totake a look at.
DR. MARKS: Hm. Oh, I understand the reasoning.
DR. HELDRETH: So, it was just a matter of trying to make this as simple as possible because it’s been an ordeal.
You know? And we’ve even brought in -- like you said, even the SASSI folks have come in and are still confused
as to which goes with which. That’s why we -MS. BURNETT: I mean, certainly we could keep them in. I mean, I’ve done an initial search and I will do anothersearch and see if there’s anything new.
So, it’s totally up to you. If you think it’s going to cause more headache, then we can take them out. If you thinkthat we’ve already gone through the headache, we can just pop a couple aspirins and keep going.
DR. MARKS: Well, I don’t -- Ron and Tom? Was there anything when we looked at these before other than reallyin the inhalation issue and silicosis?
DR. SHANK: That was all. That was all we had.
DR. MARKS: And it’s going to be interesting, because I think, ultimately, it’s going to be an insufficient data -- orinsufficient because we won’t be able to get the composition, probably with a surety, that there’s no mined silica. If
we got that, I think we could move forward in any and all of these. Is my interpretation correct?
DR. SHANK: You could say safe as used if there’s no mined product.
DR. MARKS: Yeah, there you go. So, you see how we word it around? And that’s -- why didn’t I think of that?
But I was only thinking off the top of my head. Exactly.
DR. ANSELL: Isn’t that where we divided this into three groups? Because, each silicate group, we have expansive
inhalation toxicology and were prepared to move them forward; but not so for -- but we’re uncertain about some ofthe other groups?
DR. MARKS: Okay, Jay. So, which group do you think -- do we have enough inhalation tox we can say that byreading across -- I think, whether we put that in the conclusion, Ron, or not, it will certainly be in the discussion in
great detail.
So, we’ll be looking at this again with -- but that’s a good point you bring up. Obviously, it’s back to our -- the datais what we want first. And if we have inhalation data that suggests in the present use and concentration, it’s safe,
then mined becomes almost a new subject.
Is there anything more, Christina, you wanted from us other than moving that the three groups are okay and toproceed? And I would say include everything you have here, even the red, and then sort it out later.
DR. PETERSON: Yeah, I guess that makes sense to me, too.
DR. MARKS: Does that sound good, Lisa?
DR. PETERSON: Yeah, I got very confused by the “no brainer” statement, and then why some things werecrossed out and some things weren’t.
MS. BURNETT: Yeah.
DR. PETERSON: I tried to figure it out, and I couldn’t.
MS. BURNETT: Sorry.
DR. ANSELL: Only because it is confusing.
DR. PETERSON: Yes.
DR. MARKS: Okay.
DR. HELDRETH: Yeah. Just for Dr. Peterson’s benefit -- so, when we use that phrase “no brainer,” that’s
something that the Panel has kind of used as a measurement for when we do a re-review document and we consider

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adding in additional ingredients that weren’t reviewed before. And the idea being that the data already in the current
report would support the safety of those add-ons, even if we never got any data about those new ones.
So, that’s the idea here is -DR. SHANK: No brainer.
DR. HELDRETH: -- do we know that these -- or do we think -- does the Panel think -- I’m sorry -- that these areno brainers? Are they so similar to the ingredients in the current report that we don’t need new data to call them safeor have the same conclusion?
DR. PETERSON: Okay, I understand.
DR. HELDRETH: So, that’s the idea behind that.
DR. ANSELL: And we fully support that approach. But if you put in an ingredient and then have to reopen thereport, because you can’t decide whether that ingredient is safe or not, then it falls outside of what we would
consider to be a no brainer. So, it has to slip in -- all the data in the current report has to fully support the safety of
the add-ins.
DR. HELDRETH: Right. So that’s part of the reason why when -- it fell back to CIR staff to come up withgroups. That’s why we suggested removing these ones, because it’s still completely and utterly unclear which onesof these ingredients are synthetic amorphous and which ones are potentially mined.
And we remember back when we looked at the hydrated silica and -- hydrated silica. They suggested to us that it
was synthetic. But then you read the details of the synthesis, and the first step is, it’s a mined silica and thenchemically modified. Not exactly de novo synthesis; and there is potential for having crystalline silica.
DR. ANSELL: Right.
DR. HELDRETH: So, we don’t know for any of these. Is the cosmetic ingredient only amorphous? Does it havesome crystalline potentially? Is it potentially mined, we don’t know. And that’s why we suggested deleting any
potential add-ons, because we don’t know anything about those ones either.
DR. MARKS: Well, I think the conclusion’s going to be the same for all of them. And that uncertainty is going tolead us to either an insufficient conclusion or a conclusion, safe as long as it contains no mined silica or crystalline
silica.
And that’s another way of -- unless, Jay, you have the inhalation toxicity studies on individual ingredients here thatwould support its safety.
DR. ANSELL: Well, yes. The presence of crystalline silica is a real issue.
DR. MARKS: Yeah.
DR. ANSELL: And that’s why we fully support the separation of these.
DR. SLAGA: That’s why I think they should be in separate reports.
DR. ANSELL: Right.
DR. SLAGA: I don’t like to mix strong against safe.
DR. MARKS: Pardon?
DR. SLAGA: I don’t like to mix something that has really potential health problems with something that is safe.
That kind of dilutes the safe.
DR. MARKS: Well, that’s why we split out in silica and hydrolyzed. But do you want to, right now, go to three
separate reports? Or you want to kind of move forward and then let’s see what it comes down to with -DR. SLAGA: Let’s see what it comes down to.
DR. MARKS: Okay. Is that okay, Ron?
DR. SHANK: Yes.

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DR. MARKS: And Lisa, okay with you? Okay. So, move three groups okay, one report, include all the
ingredients including the add-ons. And then we’ll see where we go.
MS. BURNETT: And you said separate reports or one?
DR. MARKS: No. One report at this point.
MS. BURNETT: Okay.
DR. MARKS: We don’t care.
DR. HELDRETH: I think, separation within the report.
DR. MARKS: Oh, yeah. Absolutely. To me, it just makes it easier in some ways if it’s all grouped together.
DR. SLAGA: It makes it easy. Right. It does.
DR. MARKS: Oh, listen.
DR. SLAGA: Yeah.
DR. MARKS: Christina’s fine, if she can get through citrus. This is a piece of cake compared to citrus and all that
stuff, huh?
MS. BURNETT: Yeah.
DR. MARKS: Okay. Any other comments? So, I’ll move three groups are fine, one report at this stage. Include
all the ingredients including the add-ons, and then we’ll see where we go from there. Okay. Let me save this. So,
we’ll see what the Belsito team thinks tomorrow. Okay.
DR. HELDRETH: One more thing on this one.
DR. MARKS: Sure.
DR. HELDRETH: I think industry had suggested, if we were keeping any of the stuff in clay groups, that we
actually review the ingredient clay since some of these things, like hectorite or whatever, are just subgroups of that
one in there.
Should we go ahead and throw that one in there since we’re going to be reviewing all these clays anyway?
DR. MARKS: I think that’s fine.
DR. SHANK: Okay.
DR. MARKS: Let’s include it now, and we could always -- I guess part of that is thinking of you, Christina. If wethrow clay in there, does that add a lot more work for you? Although, if it’s a safety concern, work is not the issue.
MS. BURNETT: It won’t be a problem. I’m more worried about generic searches and -DR. MARKS: On clay?
MS. BURNETT: Yeah. But we’ll figure it out. It’s got to be done at some point, so why not now?
DR. MARKS: Yeah. Okay.
DR. HELDRETH: Thank you.
DR. MARKS: Maybe adding clay, Tom, will then force us to go into three groups. Clay will be too big. Okay.
Full Panel Meeting – December 10, 2019
DR. MARKS: So, this is on Page 61 of the Admin folder. And, what is being proposed is that we have threegroupings of the silicate ingredients. As you recall, in the September meeting a final safety assessment ofsynthetically manufactured amorphous silica and hydrated silica are safe when formulated to be non-irritating.
The other silicate ingredients, we were concerned about chemical characterization, method of manufacturing, source
if mined and whether it’s amorphous or not. And that all led to obviously the potential toxic inhalation effect of thesilicosis.

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So, we have already opened these ingredients. Christina listed them under the group, silicates, clays and zeolites,
and we concur with that grouping.
There was a discussion whether or not to add the proposed ingredients, they were in red and crossed out. We liked
adding them since we’re going to look at these different groups.
And then there was a discussion as to whether or not -- so we liked the three groups; do we do one report or multiple
reports? And we fell on the side of doing one report just divided in the three sections, but that’s not a hard and fast.
DR. BERGFELD: Belsito response?
DR. BELSITO: Well, we liked the groupings. We agree not to include those that were suggested to be eliminated.
We didn’t see the reason for eliminating them.
We did not specifically discuss the issue of putting them into one report and three separate headings. But justthinking about how mind-boggling this is going to be, I would prefer to have three separate reports, personally.
DR. LIEBLER: If we have one report we’d effectively be converting silicates to algae.
DR. MARKS: I’ve likened it to citrus. Christina, she did such a good job with citrus, I figure she could have
handled it.
DR. LIEBLER: We’ve been there and done that.
DR. MARKS: Yeah, as I said, we didn’t have any strong feelings one way or another, so separate reports are finewith our team.
DR. BERGFELD: So, acceptance of the list with the deletion, three different categories and three different reports.
DR. MARKS: Yes.
DR. BERGFELD: I call the question, all those in favor of that decision? Thank you, unanimous.

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MARCH 2022 PANEL MEETING – DRAFT AMENDED REPORT
Belsito’s Team Meeting – March 7, 2022
Dr. Donald Belsito: So we're moving on to Clays. So this is the last of the group that we split out from silicates via(inaudible) clays, and really this is the first time we're looking at it. We split it out. We asked for mean and range ofparticle sizes. And corresponding sizes in final formulation, particles, chemical characterization, composition,
impurities and method of manufacture, source data. But that was just I guess a wish list really so now we've got tolook at what data we have here. There's also wave three comments from the Council, and we know that Kaolin isused in airbrush device. From wave 2. So in the ingredients listed activated clay and clay. We have absolutely nodata. And the definition of activated clay as it it's chemically synthesized aluminum silicate and sulfuric acid andheat. And the question I have is this forming crystalline silica? And for clay, we have zero data and just the main
ingredients being hydrated silica and aluminum. We don't have a clue what the other ingredients are.
Dr. Dan Liebler: So I think that considering the structure of clay is helpful here. You know which starts at the topof PDF 82 with that diagram. With a multi-layer silicate sheets. And then some coordinated other atoms.
That this sheet like structure is distinct from the hexagonal crystalline structure of crystalline silica, such as quartz.
And I think that we should not necessarily assume that these mined ingredients are toxicologically equivalent tomined crystalline silica. Like quartz. So it's a similar concern I had to our interpretation of the chemistry as in the
diatomaceous earth report. It's not all. Not all silica containing materials are created equal.
Dr. Donald Belsito: OK. And are you happy with the method of manufacturing that is given this is PDF 82 goingon to 83? Or do we need better data for cosmetic grade materials? More complete composition for clay.
Dr. Dan Liebler: Well, I mean, I think these are all essentially. At least the ones that are listed are all mined,
washed, filtered, ground. etc. So that's what we're given with these. Let me look at the full list. So we got attapulgite
and bentonite. Kaolin. Yeah. Bentonite Hectorite Montmorillonite. So you got virtually all of them listed as mined,
essentially, mined washed and or I'm sorry that that's the descriptions. Yeah, I'd like to. Now, let me see here. So we
don't have any explicit description. Of the manufacturer for the ones other than the ones that are listed. So we've got
attapulgite. Kaolin. And I think it's hectorite?
Dr. Donald Belsito: Bentonite.
Dr. Dan Liebler: Bentonite. OK, so the others? We should be able to at least confirm that they are mined, and notsynthetically produced.
Dr. Donald Belsito: Well, activated clays, apparently synthetically produced.
Dr. Dan Liebler: Are you getting that out of table one?
Dr. Donald Belsito: Yeah, I think so.
Christina Burnett (CIR): Based on the definition.
Dr. Donald Belsito: Yeah.
Dr. Dan Liebler: Oh, inorganic compound obtained by heating natural aluminum silicate with sulfuric acid. Yeah,
if this isn't mined and it's not demonstrably structurally similar or identical with the other clays. It probably should
be deleted from the report.
Christina Burnett (CIR): So delete activated clay?
Dr. Dan Liebler: Yeah, we delete it unless we can show that it belongs with the other ingredients. Either by virtue
of its structure. You know, well characterized information on the structure or the method of manufacture beyond
what's in the table. It's an entry in the table suggests that it doesn't belong.
Dr. Paul Snyder: We thought the botanicals were a ******.
Christina Burnett (CIR): Oh my God.
Dr. Paul Snyder: So I had. I thought these were all safe as used because clay is GRA in indirect food additives.
Except for inhalation, and I think the inhalation issues surrounds the insufficient date announcement that mean rangeof particles, the chemical composition, impurities, data and method of manufacturing source data. I thought we wereDistributed for Comment Only -- Do Not Cite or Quote

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still stuck there because I don't think we have any data on some of these. Or insufficient data, but I thought for only
for inhalation. Incidental inhalation, I thought for. Although the uses that either were OK, it goes safe as you.
Dr. Dan Liebler: Yep.
Dr. Paul Snyder: Kind of the same. I mean, it's the same ****** to me.
Dr. Dan Liebler: Yes, we don't have any inhalation tox on these.
Dr. Donald Belsito: Right.
Dr. Dan Liebler: Yeah. So that's what that's what saved us with the, with the diatomaceous earth report, because we
did. Here we don't and I wouldn't support the same approach that we took at diatomaceous earth. I think we would
need to raise a concern about inhalation. Safe is insufficient for (inaudible) potentially inhaled products. I mean, we
do know on the other hand that clays are structurally distinct. From the silicate structures that we associate withpulmonary toxicity, but if we don't have. You know, then it's just a question of, do you? I think the analogy tosilicates. Doesn't necessarily hold up chemically. But then the lack of any inhalation tox still raises a, I think alegitimate concern. Is that where you are, Paul?
Dr. Paul Snyder: Yeah, I mean, I mean, I. Yeah, I mean it's just the same, same old, same old, you know, it's justthere's just no inhalation data and there's no impurity data or chemical composition or reap range of particle size or
anything.
Dr. Donald Belsito: Well, we know that Bentonite can contain crystalline, it says from the documents.
Dr. Curtis Klaassen: I think there was an intratracheal study I remember.
Dr. Donald Belsito: Or yeah, we had carcinogenesis studies. This is the one Paul where all the inhalation
carcinogenicity.
Dr. Dan Liebler: PDF 86-88.
Christina Burnett (CIR): No, it's for Attapuligite (inaudible). And Attapulgite has the IARC designation for atdifferent fiber lengths.
Dr. Donald Belsito: We also have montmorillonite (inaudible).
Christina Burnett (CIR): That's the *(inaudible) study.
Dr. Donald Belsito: We also Christina need to update the concentrations of use. The last data we have is 2018.
Christina Burnett (CIR): I forget to do that? The concentration of use means… that's the data that I have. Council
will have to do a new survey.
Dr. Donald Belsito: Yep. Do we know if that's under works?
Christina Burnett (CIR): I don't.
Carol Eisenmann (PCPC): It is not in the works.
Dr. Donald Belsito: Thank you, Carol.
Dr. Donald Belsito: So where are we with these here? With this, with these carcinogenicity studies? Are they
helpful? And should they be moved to the toxicity section?
Dr. Dan Liebler: We awaiting judgment by Paul or Kurt.
Dr. Curtis Klaassen: Well, I think it's appropriate, but have it where they are at because, they really are. This
attapulgite. Is ah. You know, I think they this this group of chemicals maybe have a greater concern in regard tolung and lung cancers and some of the other components that we've been looking at. I mean, you can see here that.
Dr. Paul Snyder: A lot of lung cancer.
Dr. Curtis Klaassen: They did a yeah, and there's some nasty ones. You know, they got a parenteral, mesothelioma,
adenocarcinoma, three bronchiolar hyperplasia and not so bad. Ah. And the mesothelioma.
Dr. Dan Liebler: Yeah.

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Dr. Curtis Klaassen: Like mentality, older neoplasia. I mean, I think. They had a fall guy that we definitely don't
want to have.
Dr. Paul Snyder: Can you send me that study, Christina, please? Report.
Christina Burnett (CIR): I will have to find it because these are from the original report, yeah.
Dr. Paul Snyder: Oh, OK, that's right.
Christina Burnett (CIR): But I can look.
Dr. Curtis Klaassen: Panel that says under the kaolin right underneath it is it was used as the negative control.
Christina Burnett (CIR): Correct.
Dr. Curtis Klaassen: Ah. And they. They had two bronchiolar alveolar tumors were reported.
Dr. Donald Belsito: OK.
Dr. Dan Liebler: So Don, the previous discussion which is on PDF 96 is kind of interesting. It was put up there forour consideration. A panel. I'm just reading a little bit panel did note concern about inhalation of these ingredients
due to a report in case of pneumoconiosis and fibrosis in humans and pulmonary lesions in animals. However,extensive damage in humans was the result of direct occupational inhalation of a dust and lesions and animals wereaffected by particle size, fiber length and concentration. So the panel basically said that most of these formulations
aren't respirable and the preparations that are respirable the concentration of the ingredients are low. So even so, thepanel considered spray containing these solids should be formulated to minimize inhalation. So, in other words, on
all sides of the issue.
Dr. Donald Belsito: I mean, this is not my area of purview, by the way, we have no sensitization data, but it's notgoing to pass the stratum corneum so we can argue that in the discussion. So, I wouldn't push for that.
Dr. Dan Liebler: I mean in, you know, given the data that we have in, in, in front of us at this stage of the report. I
suppose. You know, I guess we could consider an IDA. More inhalation tox. I don't know if that's needed it, given
the data that we already have from the old report. The data from the old report, I think we would probably now havea conclusion that says safe as used except for products where incidental inhalation may occur.
Dr. Donald Belsito: Right.
Dr. Paul Snyder: In the absence of Impurities, composition and Inhalation tox toxicity studies, right.
Dr. Dan Liebler: Yeah.
Dr. Donald Belsito: Well, we have products where incidental inhalation, we have products that may have incidental
inhalation. So. I mean, this is a first pass, so I guess the first question I have is, are we getting rid of activated clay
because it's manufactured and not mined?
Dr. Dan Liebler: We don't have enough description of the final material to show that it actually belongs with therest of these. It's called activated clay, but it may not really be like the other clays.
Dr. Paul Snyder: So we should.
Dr. Donald Belsito: OK, so we're getting rid of this.
Dr. Paul Snyder: So should the title, be natural, naturally sourced clays.
Dr. Donald Belsito: Sure. OK. So, we're going to get rid of the activated clay, we’re happy with the manufacturing?
Dr. Dan Liebler: I think other than that, we are. Interestingly, activated clay has no reported uses no concentrations.
Dr. Donald Belsito: Right. Right. So we're happy with manufacturing. What about impurities?
Dr. Dan Liebler: Taking another look real quick. I think we’re satisfactory on it. Composition, impurities.
Dr. Donald Belsito: The bentonite has cristobalite.
Dr. Dan Liebler: Right.
Dr. Donald Belsito: OK and carcinogenicity data. How are we dealing with that?

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Dr. Paul Snyder: Well, I think this one, this is I think a little bit different here is that for these, we really want toknow the particles, mean and range of particle size distributions, right? More so than the more so than impurities.
Dr. Donald Belsito: OK. So is it insufficient for mean and range of particle size distribution?
Dr. Paul Snyder: I think at this stage, yes.
Dr. Donald Belsito: There as long as we're asking for that, we can ask for skin sensitization. We don't have any.
Dr. Dan Liebler: Yeah. For Bentonite, we do have some particle size information on PDF 83. It says 90% of theparticles were smaller than 68 microns, 50% smaller than five microns.
Dr. Donald Belsito: Yeah.
Dr. Dan Liebler: I don't think it will boil out like incidental inhalation.
Dr. Donald Belsito: It’ll be the heavy metal boilerplate in discussion. OK, so we are insufficient for mean and rangeof particle distribution except for Bentonite?
Dr. Dan Liebler: Right.
Dr. Paul Snyder: Well. Yeah. I mean, it's 60% of them are for sure under 10 microns.
Dr. Dan Liebler: That's for bentonite.
Dr. Paul Snyder: Yeah.
Dr. Dan Liebler: Yeah, I mean it, I don't object to asking for it even if we have it, but it doesn't mean it doesn't tell
us what the particle size distribution would be in the product that contains you know, the clay.
Dr. Donald Belsito: We want particle distribution and final product.
Dr. Dan Liebler: Yeah, nobody is going to have that.
Dr. Donald Belsito: Right.
Dr. Bart Heldreth (CIR): You actually asked for that before. At the top of the memo, on PDF Page 3.
Dr. Donald Belsito: Yeah.
Dr. Dan Liebler: Yeah.
Dr. Bart Heldreth (CIR): It's the first data need.
Dr. Dan Liebler: Alright, well we can keep it in and then decide whether we you know. But I mean our discussions
public record so.
Dr. Paul Snyder: I mean, like I said before, it's for me there's safe as used. Other than that incidental inhalation
Dr. Dan Liebler: Yeah because, you've got all this tracheal installation, carcinogenesis carcinogenicity, right. So
that's that's the fly in the ointment right there.
Dr. Donald Belsito: OK so. We're asking for particle size. This range and distribution for all except Bentonite andthen.
What are we asking to clear the inhalation that we're saying is the issue. We have these carcinogenicity studies.
Christina Burnett (CIR): You have it on one, not the others, correct
Dr. Donald Belsito: Right, we have it on attapulgite?
Dr. Paul Snyder: It's just going back to the previous discussion, Don, on Page 96 where we want to, we want to say
the that the formulations are not respirable. So, we need to know what the range of particle sizes are and productpreparations are respirable the concentration in the ingredients is very low.
Which I think is not quite how we've handled it now is it updated? But.
Dr. Donald Belsito: We pretty much know that attapulgite should not be in products that could be inhaled.
Dr. Paul Snyder: Bentonite because most of the particles are less than. Less than 10 microns.
Dr. Donald Belsito: Or. And it also has a lot of cristobalite. Kaolin seems to be OK. It was the negative control.

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Dr. Paul Snyder: But is it Kaolin and the one that's used in airbrushes?
Dr. Dan Liebler: So we'll just need our airbrush discussion boilerplate once we adopt it.
Dr. Donald Belsito: Heavy metal. So what I have here is insufficient for median range of particle distribution for all
except Bentonite. Which leaves what all except Attapulgite. No. All except Bentonite, right?
Dr. Dan Liebler: Yep.
Christina Burnett (CIR): Correct.
Dr. Donald Belsito: Attapulgite and bentonite should not be in products that could be inhaled. And airbrushdiscussion boilerplate. Dermal all we have is a negative irritant study in hectorites. So, we want sensitization
irritation and concentration of use as long as we're going forward.
Dr. Dan Liebler: I think the inhalation data requirement is everything except Kaolin, right?
Dr. Donald Belsito: Well, do we want them to repeat that attapulgite?
Dr. Dan Liebler: Oh no. Right. Unless you think that tracheal (inaudible). Actually, the data we have and the
carcinogenicity section for attapulgite includes inhalation and parenteral OK, yeah.
Dr. Donald Belsito: And Bentonite contains cristobalite. We want an inhalation study on that.
Dr. Dan Liebler: Yeah.
Dr. Donald Belsito: We do.
Dr. Dan Liebler: I think so.
Dr. Paul Snyder: Yeah, at this pass, yes.
Dr. Donald Belsito: So it's…
Dr. Dan Liebler: I mean, you know, we will have an inhalation reason to dissociate any of them. Without having
data and Kaolin is the one that was inhalation as a negative control and it behaved that way. So we don't have thatkind of data for anything else. So Attapulgite's documented with respect to producing tumors and so forth, the others
have no data one way or the other. So, I think they, you know, they belong with an insufficient data requirement.
Dr. Donald Belsito: So maybe we need. Excuse me, do we need chronic inhalation for kaolin? Was used as thenegative control and was negative.
Christina Burnett (CIR): I did find that study.
Dr. Dan Liebler: Yeah.
Christina Burnett (CIR): I could send it on to whomever would like it.
Dr. Paul Snyder: I would like it please.
Christina Burnett (CIR): OK, Dr Snyder, right.
Dr. Paul Snyder: Yes, please. Thank you, Christina.
Dr. Donald Belsito: Well, chronic inhalation for all except attapulgite and kaolin right now.
Dr. Dan Liebler: So. Right.
Dr. Donald Belsito: So we're dropping activated clay. We're asking for mean and range of particle distribution for
all except Bentonite. We’re asking for chronic inhalation for all except attapulgite and Kaolin. And we’re asking forsensitization, irritation and the maximum concentration of use. Which is what 7% is that right?
Monice Fiume (CIR): I'm sorry, Kaolin is used that up to 53% in manicuring preparations.
Dr. Paul Snyder: Those are manicure preparation.
Monice Fiume (CIR): Bentonite 15% in skin care preparations.
Dr. Paul Snyder: Yeah.

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Dr. Donald Belsito: So (inaudible) at 15% in Bentonite? And the discussion, heavy metals? And Airbrushtechnology and that attapulgite and bentonite should not be used in products that could be inhaled based upon the
carcinogenicity studies. Without attapulgite and the cristobalite concentration in bentonite. Is that correct?
Dr. Paul Snyder: And particle size distribution in bentonite also. So that for the other ones, if we get particle size
distribution says not respirable, then we don't need the chronic inhalation studies.
Dr. Donald Belsito: Yep. For bentonite, it's because of cristobalite and particle size.
Dr. Paul Snyder: Correct.
Dr. Donald Belsito: And for attapulgite, it's because of data.
Dr. Paul Snyder: Correct.
Dr. Donald Belsito: Anything else for this?
Dr. Curtis Klaassen: So eventually with attapulgite it we know that it can cause tumors. So in the end, will wemost likely say that it's OK to use, but we just need to minimize the inhalation exposure?
Dr. Donald Belsito: We're already saying that in the discussion.
Dr. Curtis Klaassen: OK.
Dr. Donald Belsito: They both attapulgite and bentonite should not be in product.
Dr. Curtis Klaassen: So yeah. Being the Devil's advocate a little. Done with all of the other compounds. Why do
we want to do a chronic study of carcinogenicity. Because they'll have the same conclusion one way or the other.
Dr. Donald Belsito: Well, we have Kaolin and it's negative. So, we don't know what the others are going to be.
Dr. Curtis Klaassen: Then we could. We won't say anything about *(inaudible).
Dr. Paul Snyder: We could have a *(inaudible) size, Curt, then we don't have to worry about it.
Dr. Curtis Klaassen: But they're all going to be in the right size.
Dr. Paul Snyder: I think you're right.
Dr. Donald Belsito: Well, let's see what we got. I mean, it's, it's insufficient. Do we need any other data needs so
insufficient mean and range of particle distribution for all except Bentonite? The chronic inhalation for all except
Attapulgite and Kaolin. And dermal sensitization irritation at 15%, Bentonite and already in the discussion heavy
metals, the attapulgite and bentonite not in products that could be inhaled, attapulgite because of the carcinogenicity
studies, bentonite because its cristobalite content, particle size and also discussing airbrush technology discussion
boilerplate. That's what I have.
Dr. Paul Snyder: I think you have it.
Dr. Donald Belsito: OK. Let's move on, folks. It's 3:15. We still have two. One being, botanicals.
Dr. Curtis Klaassen: Thanks.
Dr. Donald Belsito: Christina, any questions?
Christina Burnett (CIR): No.
Cohen’s Team Meeting – March 7, 2022
Dr. David Cohen: OK. Yeah. Look, I told you the out of the gate with these were a little tough, so we have let's wewant to move on to Clay.
Christina Burnett (CIR): Sure.
Dr. David Cohen: So, this is used as a skin conditioning agent and it's used a fair amount and in 2018 the panel
reopened a 2003 safety assessments for several silicates, clays and zeolites. At I think that meeting Don had
suggested splitting off clays on their own. That was probably a very good recommendation. And at that meeting but
insufficient data was described for eight clay ingredients, asking for particle size ranges that are used in sprays andDistributed for Comment Only -- Do Not Cite or Quote

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powders, chemical characterization of composition, method of manufacturing. We have updated VCRP information.
And there's a mention about this discussion about pneumoconiosis. And the second wave data, we see clays used inairbrushes. And in impurities, there's no mention of crystalline silica, but I think there's a comment about it in the
bentonites section. So, and the third wave of edits from PCPC were great. The constituents didn't seem to alarm me
for irritants or allergens. What do you think, Tom you want to start?
Dr. Thomas Slaga: Ah, yeah, well, since the last meeting, we really haven't received any new data. So you know
particle size and all of that, the chemical characterization, etcetera. It's the same, so same conclusion as last time.
Unless I missed data? But what I see is that we didn't receive any.
Christina Burnett (CIR): No, we didn't.
Carol Eisenmann (PCPC): But, this is Carol. Sorry to interrupt, but, method of manufacture for this doesn't makesense. Mainly you dig it out of the ground and clean it up. I mean, what, what more can you say about Clay?
Dr. Thomas Slaga: Ah. I didn't ask for that. I think the 1st 2. The particle size and chemical characterization that'smore important. The method I agree with the method of manufacturing, it's not really needed.
Dr. David Cohen: I put it since this predated me it if we had this and this was new for us. This was just a newreport on clay. Without the prior IDA or bias from that. What would you? How would you come out on this? What?
What would you want to know? And if we knew it was being used in a spray product in an airbrush, we would
simply split the conclusion out that there's insufficient data for airbrush. But what part of this report do you still needor want irrespective of the idea in the past?
Dr. Thomas Slaga: I don't think I would need any.
Dr. Wilma Bergfeld: I thought it was missing the molecular weight.
Dr. Thomas Slaga: *(inaudible) That's where I would go. So but we do have the IDA with those requirements andwe have to you know either get something or find a reason why we don't need it. That's where we're at right now.
Dr. David Cohen: Well, no. You said something that you need we needed something?
Dr. Wilma Bergfeld: Well, I just said that I had the old document that I was reviewing and a lot of the chemical
information is in the old document including molecular weights. And I didn't really see all of that in the new
document.
Which may or may not help the chemists, but they are ranging from 100 to 350 in molecular weight. And they havefull description of the actual chemicals in the old document. We're still missing some of the human stuff.
Sensitization, I recall.
Christina Burnett (CIR): Right. There is no, there's no sensitization data.
Dr. Ron Shank: Yeah, we don't have it.
Dr. Wilma Bergfeld: No, no. Yeah, I have it listed here.
Dr. Ron Shank: We didn't ask for it last time. Why?
Christina Burnett (CIR): Well, last time you looked at it was all lumped together with the silicates and silica. I felt
the focus at that time was on those ingredients. And these were kind of not really discussed at that time.
Dr. Ron Shank: OK.
Christina Burnett (CIR): It was a big report last time, so I understand.
Dr. David Cohen: So.
Dr. Ron Shank: Well. I thought there was, these are large, large molecules are not likely to penetrate theepidermis. So I don't have a systemic toxicity concern, apparently they can be formulated, or the formulators canchoose. Clays. That can be, I don't know if it's certified. But claimed to be free of crystalline silicate. I understoodthat from the report. I think the inhalation can be handled by the boiler plate. So the. The only serious lack I saw wassensitization.
Dr. David Cohen: Right, so when I.
Dr. Ron Shank: That'll probably surprise everybody.

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Clays – Expert Panel for Cosmetic Ingredient Safety Meeting Transcripts

Dr. Wilma Bergfeld: I would think irritation too.
Dr. Ron Shank: OK, I put those together.
Dr. Wilma Bergfeld: Yeah. OK.
Dr. David Cohen: Yeah, I mean, I think when I looked at the constituents, I'm like I don't. Expect much in the wayof sensitization, but it's possible here because there's some minerals there, so we'll ask for sensitization and irritationand sensitization.
Dr. Thomas Slaga: Yes.
Dr. Ron Shank: Yes.
Christina Burnett (CIR): Yes. If you would like, you can just, when you issue the new IDA, you can ask for theprevious items again to minus the method of manufacturing. If you believe that's not needed.
Dr. Ron Shank: Well, I thought we had that.
Dr. David Cohen: And then.
Dr. Thomas Slaga: Yeah.
Christina Burnett (CIR): Yeah.
Dr. David Cohen: Wait, so do we?
Christina Burnett (CIR): We have the method of manufacturing for attapulgite, bentonite and kaolin. Strip mined
and then cleaned up a little bit.
Dr. David Cohen: OK so as same as before last method of manufacturing for the ones we have. And we want
irritation and sensitization data and would we still split the conclusion, I mean it it's in, it's in airbrush material.
Dr. Wilma Bergfeld: Correct.
Dr. Bart Heldreth: Well, and since you're putting out an insufficient data announcement, you don't really have to
put out a conclusion yet.
Dr. David Cohen: No. I know I think just during tomorrow we would discuss airbrush, right? We're not going to
split anything because there's no conclusion to split. But this this data. Anything else on this one?
Dr. Thomas Slaga: No.
Christina Burnett (CIR): Because it will come up eventually.
Dr. Wilma Bergfeld: Well.
Christina Burnett (CIR): Possibly. I don't know, I mean. I did note in the report that the IARC and the California
board had flagged attapulgite for fiber lengths greater than five micrometers. Is that anything that will need to be
discussed in the future?
Dr. Ron Shank: Yes.
Christina Burnett (CIR): OK. Do we have anything to actually…How did you want to state anything? Did you
want it similar to eronite where you expect that it's not to be used or controlled?
Dr. Wilma Bergfeld: Should be similar.
Dr. Ron Shank: Well, long fibers. It's a matter of fiber length.
Christina Burnett (CIR): Yes it appears.
Dr. Ron Shank: So long fibers should not be used and apparently of the formulators can choose (inaudible) that
don't have long fiber. Attapulgite.
Christina Burnett (CIR): OK.
Dr. David Cohen: In it may come up also on page 95 under Bentonite. I think it's in the occupational exposure
section.

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Clays – Expert Panel for Cosmetic Ingredient Safety Meeting Transcripts

It says, however, because some forms may contain variable amounts of respirable crystalline silica, prudent
management, inherent occupational exposure limits as appropriate. So are we going to get into the crystalline silica
thing here for Bentonite?
Dr. Wilma Bergfeld: I think so.
Dr. Ron Shank: Yes.
Dr. Wilma Bergfeld: You have to discuss it at least.
Dr. David Cohen: Yeah.
Dr. Wilma Bergfeld: In the old document it also says that clay has a great ability to absorb.
Christina Burnett (CIR): So yeah, it there was a very long section on how they use it to clean up, you know,
pollution and use it in all sorts of things just to pull toxins out.
Dr. Wilma Bergfeld: Adsorbed then.
Christina Burnett (CIR): Adsorbed yeah.
Dr. David Cohen: Message not otherwise specified.
Christina Burnett (CIR): Yes, so that information.
Dr. Ron Shank: That's not a cosmetic use.
Christina Burnett (CIR): Correct. It was included in the old report, I believe, you know, we put a lot of
information that we don't use anymore in those.
Dr. Wilma Bergfeld: Well, that I don't think that I think we conclude I think that there could be used in a cosmetic.
Dr. David Cohen: Oil absorption. Yeah, oil absorbing.
Dr. Wilma Bergfeld: There, yeah.
Dr. David Cohen: Oil absorption, providing a matte sheen right, and that's maybe all part of clay.
Dr. Wilma Bergfeld: That's what the masks do.
Christina Burnett (CIR): I can't remember if, did I completely remove that because I can just... Yeah, I put just it's
good adsorption performance in the non cosmetic use section. Is that sufficient? OK.
Dr. Ron Shank: Yeah, that's alright.
Dr. Wilma Bergfeld: Right. The other thing is that I I'm trying to think where I wrote this down at some of theseare GRAS ingredients and the question was whether they're used as nanoclays in cosmetics. And that kaolin is foodgrade. So we have maybe to deal with the GRAS ingredients in the in the discussion.
Dr. Ron Shank: Yeah. Well, we don't need systemic tox data.
Dr. Wilma Bergfeld: Bentonite. What? No. That's right, Bentonite. Yeah, I was the one, I think.
Dr. David Cohen: Bentonite was the oral one.
Dr. Wilma Bergfeld: Yeah. So one of the GRAS and the food additives are indirect are the silicates.
Dr. David Cohen: OK. So we're going to go with the IDA as we suggested, they'll be a lively discussion about othercomponents of this. And the report will proceed along. OK.
Full Panel Meeting – March 8, 2022
Dr. Don Belsito: OK so basically this was split out of the silicates, clay, and zeolite report in 2018 and it's really the
first time that we're seeing this package on Clay. We do have a good amount of information in the package, which
we viewed. And basically inhalation and heavy metals are going to be the focus with this report. The first thing isthat activated clay appears not to be mined, but rather manufactured and Dan recommended it be dropped from thegroup and then for the other remaining clays, they're insufficient for mean and range of particle distributions. For all
except bentonite. Attapulgite or bentonite should not be in products that could be inhaled. Attapulgite because of

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Clays – Expert Panel for Cosmetic Ingredient Safety Meeting Transcripts

the carcinogenicity data, bentonite because of its content of cristobalite. The airbrush discussion in the boiler platethat we've discussed. Dermal, all we have is a negative irritant study on hectorite. So we want sensitization andirritation of 15% bentonite, which is the highest uses and we want chronic inhalation for all except attapulgite andkaolin Attapulgite already known to be positive and kaolin was used as a negative control in those studies. So get ridof activated clay and insufficient. For the reasons that I gave.
Dr. Wilma Bergfeld: David, comment?
Dr. David Cohen: Digesting. That was very comprehensive and I think checked off everything we had. Don, youmentioned the respirable Crystalline silica in the bentonite.
Dr. Don Belsito: Yeah.
Dr. David Cohen: While the constituents don't necessarily alarm us for allergens, we wanted irritation andsensitization, how you mentioned it.
Dr. Don Belsito: Yeah, I mean it's a wish list. We asked for it.
Dr. David Cohen: So. Yeah. Yeah, I would second the Belsito team motion.
Dr. Wilma Bergfeld: Any other comments about pulling out the activated clays?
Dr. David Cohen: We didn't discuss that and that was interesting. Ron and any comments that seems to make sense
to me because we commented on the method of manufacturing which is pulling clay at the ground and cleaning it
up. Ron, Tom, what do you think? I'm OK with pulling that out.
Dr. Ron Shank: Great.
Dr. Thomas Slaga: I am too.
Dr. Ron Shank: I have no objection.
Dr. Wilma Bergfeld: Ron. Dan, could you describe why you pulled it out?
Dr. Dan Liebler: From the definition of briefly indicated in table one, I think it is. It's an inorganic compound
obtained by heating natural aluminum silicate with sulfuric acid. So, this is really distinguishes it from all of theother mined ingredients and because there's not much description of what it is, does it have the same kind of lattice
structure and everything? I felt that there, you know, the burden would be on industry to demonstrate that thismaterial belongs in the same category as these others.
Dr. Ron Shank: OK.
Dr. Wilma Bergfeld: OK.
Dr. Paul Snyder: We also discussed changing the title then to naturally sourced clays.
Dr. Don Belsito: Right.
Dr. Wilma Bergfeld: OK.
Dr. David Cohen: Ah, that's a that's a good idea.
Dr. Wilma Bergfeld: Yeah. It's so general agreement changing the title. Yes, I gather. OK.
Dr. Dan Liebler: Yep.
Dr. Wilma Bergfeld: OK, so we had a second on a data, a conclusion of insufficient data with all the insufficiencies
described and pulling out the activated clay. Christina, do you have a comment?
Christina Burnett (CIR): Yeah, I just want to read back what the data needs are to make sure I got it done right. I
have dermal irritation and sensitization at maximum concentration of use, which was the one for bentonite.
Dr. Don Belsito: 15%.
Christina Burnett (CIR): 30%. Chronic inhalation studies on all except attapulgite and kaolin. And then particle
size distribution for all of them. Except for bentonite. Is that correct?
Dr. Don Belsito: I'm. I'm just checking here. Yeah, I mean, and range of particle size distribution for all except
bentonite, right, Christina?

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Clays – Expert Panel for Cosmetic Ingredient Safety Meeting Transcripts

Dr. Paul Snyder: That's correct.
Christina Burnett (CIR) : OK.
Dr. David Cohen: And on this is going to be perfect for your new inclusion in cosmetic uses, because this is going
to come up for the airbrush.
Dr. Don Belsito: Right.
Dr. Wilma Bergfeld: Yeah. OK. Any further discussion will call the question. All those opposed. Approved.

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Aluminum Silicate, Calcium Silicate, Magnesium Aluminum Silicate, Magnesium Silicate, Magnesium
Trisilicate, Potassium Silicate, Sodium Magnesium Silicate, Sodium Metasilicate, Sodium Silicate, Zirconium
Silicate, Attapulgite, Bentonite, Fuller’s Earth, Hectorite, Kaolin, Lithium Magnesium Silicate, Lithium
Magnesium Sodium Silicate, Montmorillonite, Pyrophyllite, and Zeolite
September 9-10, 1999
Dr. Belsito noted that this group of ingredients consists mostly of clay-like materials, but that salts (i.e., Potassium
Silicate, Sodium Metasilicate, Sodium Silicate, and, possibly, Zirconium Silicate) are also included. He also
recalled studies indicating that the salts, but not the clays, were irritants, and that his Team recommended that thesefour salts should be included in a separate report. The Belsito Team also concluded that the remaining ingredientsare safe as used in cosmetic products. Dr. Belsito said that his Team will make a decision on specific data requests
after the current report has been divided into two separate reports.
Dr. Schroeter said that his Team agreed that the ingredients in this review could be separated into two groups,
soluble salts, which may be active (Sodium Metasilicate, Potassium Silicate, and Sodium Silicate) and minerals ofsolids (or clays) within the same report. He noted that the clays have no absorption and are basically safe, except forthe possibility of irritation. Dr. Schroeter also noted that cosmetic use includes sprays and that the issue of
inhalation exposure could be addressed in the report discussion as a cautionary item. Furthermore, he said that theirritation potential of clays could be addressed in the report discussion by stating that concentrations in formulationthat induce irritation should be avoided.
Dr. Andersen said that according to yesterday’s Team discussions, the principal issue concerning the soluble salts
relates to irritation. Therefore, he said that if the conclusion on this group of ingredients could reflect the need toformulate so that products are not irritating, then that concern could be eliminated.
Dr. Andersen also said that it may be possible for the Panel to issue a tentative conclusion on this group ofingredients. He recalled that, except for the issue of inhalation exposure to clays, there are no other safety issues
and, thus, the clays could be considered safe as used.
Dr. Belsito agreed that a safe as used conclusion could be issued on the clays. He also said that it could be stated in
the report discussion that data on the use of clays in aerosolized products are insufficient.
Dr. Shank expressed concern over the possibility of silicosis following inhalation exposure to dust particles.
Dr. McEwen said that silicosis is not a concern because these ingredients are not composed of crystalline silicone.
However, he noted that pneumoconiosis may be a concern.
Dr. Andersen noted that crystalline forms do exist.
Dr. Belsito proposed dividing the current document into two reports. One of the reports will contain a safe as usedconclusion on the clays and the other report on the salts will be re-reviewed as a separate document. Dr. Belsito
speculated that the issue of irritation will be the only safety issue relating to the salts.
The Panel agreed with Dr. Belsito’s proposal.
Dr. Schroeter confirmed that the issue of inhalation relating to the clays will be addressed in the report discussion.
The Panel voted unanimously in favor of issuing a Tentative Report with a safe as used conclusion (and appropriate
report discussion) on the clays.
The Panel also voted unanimously in favor of incorporating the data on the soluble salts from the current report into
a separate document that will be reviewed by the Panel.
Dr. Bergfeld stated that the report on the soluble salts will be reviewed at the next Team meeting.

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February 14-15, 2000
Dr. Schroeter stated that a Tentative Report with a safe as used conclusion was issued at the September 9-10, 1999
Panel meeting. He then noted that one of the ingredients included in this review, Magnesium Silicate, had been
considered talc, and that FDA informed the Panel that there is a considerable amount of data indicating that talc may
have carcinogenic potential and that this issue is being addressed. Dr. Schroeter pointed out that the structure and
CAS number of Magnesium Silicate are different from those associated with talc, and that this should be clarified in
the CIR report.
Dr. Belsito said that the fact that talc is not one of the ingredients in this review should be stated in the reportintroduction and discussion, and also noted that talc will be the subject of another review by the CIR Expert Panel.
The Panel voted unanimously in favor of issuing a Final Report with a safe as used conclusion on the Aluminum
Silicate ingredient family.
Because of the number of ingredients to date for which the issue of particle size (relating to inhalation or aerosol
exposure) has been raised, Dr. Bergfeld asked Dr. Belsito to review the caveat relating to particle size that has been
included in CIR reports. Dr. Bergfeld informed the Panel that this caveat will be discussed at the upcoming Panelmeeting.
Dr. Bergfeld also noted that because it is likely that the Panel will review talc at some point, the Panel’s
prioritization of this ingredient for review should be considered.
Dr. Belsito added that it is his understanding that FDA has reviewed talc and has not found that the data warrant any
immediate action. He said that talc should be added to the CIR Priority List, but should not necessarily be added at
the top of the list.
Dr. Bailey said that there are some aspects of talc that would be of interest, more so from the perspective of setting
standards or specifications for talc in terms of particle size. He noted that the results of an NTP inhalation study(animals) on talc indicated exposure-related carcinogenic effects that were attributed to particle size. In this study,
the particle size of the talc was smaller than that used in cosmetics. Dr. Bailey added that he has not reviewed any
comprehensive data that address the particle size of talc that is used in cosmetics (i.e., the particle size distribution).
In light of the NTP finding, he also said that in order for one to have a higher level of confidence relative toinhalation exposure, data on particle size distribution (in cosmetics) would be very useful.
Dr. McEwen said that the NTP study results were not linked directly to the talc, but to the overload and a secondary
mechanism. He also said that the effects of talc in miners and millers of this chemical have been studied over a
period of 50 to 60 years. The magnitude of the lung effects seen in a specific talcosis is basically pneumoconiosis,
which can be identified by the crystalline structure in X-rays. Dr. McEwen added that lung cancer has neverresulted from exposure to talc itself. However, talc that is mined from asbestiform-containing mineral deposits has
been implicated in cancer, specifically, the asbestiform particulate. According to Dr. McEwen, the specification forcosmetic grade talc indicates that it contains no asbestiform particulate.
Dr. Bailey wanted to know the extent of industry compliance with the CTFA specification for cosmetic grade talc.
He said that it would be nice to have some assurance that the standard is being implemented.
Dr. McEwen said that relevant sampling would have to be done in order to insure this.
Dr. Bailey said that the Expert Panel could request these data, and that the Panel’s efforts may be more successful
than those of FDA.
Dr. Bailey also said that another issue relates to perineal use of talc and ovarian cancer, and that, based on theavailable data, FDA has not arrived at any conclusion relative to this issue.
Dr. Bergfeld said that information relating to particle size will be retrieved from CIR reports for review. She notedthat the Panel has been faced with issues relating to aerosol exposure to cosmetic ingredients, and that previous
statements regarding particle size need to be captured for future use in safety assessments.

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Amended Safety Assessment of Naturally-Sourced Claysas Used in Cosmetics

Status:Release Date:
Panel Meeting Date:

Draft Tentative Amended Report for Panel Review
September 1, 2022
September 26-27, 2022

The Expert Panel for Cosmetic Ingredient Safety members are: Chair, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito,
M.D.; David E. Cohen, M.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; Allan E. Rettie, Ph.D.; David Ross, Ph.D.;
Thomas J. Slaga, Ph.D.; Paul W. Snyder, D.V.M., Ph.D.; and Susan C. Tilton, Ph.D. Previous Panel member involved in thisassessment: Ronald C. Shank, Ph.D. The Cosmetic Ingredient Review (CIR) Executive Director is Bart Heldreth, Ph.D.
This safety assessment was prepared by Christina L. Burnett, Senior Scientific Analyst/ Writer, CIR.
© Cosmetic Ingredient Review
1620 L Street, NW, Suite 1200 ♢ Washington, DC 20036-4702 ♢ ph 202.331.0651
cirinfo@cir-safety.org

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ABBREVIATIONSAICIS = Australian Industrial Chemicals Introduction Scheme
BAL = bronchoalveolar lavage
cfu = colony forming units
cGMPs = current good manufacturing practices
CHO = Chinese hamster ovary
CIR = Cosmetic Ingredient Review
Council = Personal Care Products Council
CPSC = Consumer Product Safety Commission
DART = developmental and reproductive toxicity
EU = European Union
FDA = Food and Drug Administration
β-GLUC = β-glucuronidase
GRAS = generally recognized as safe
HRIPT = human repeated insult patch test
IARC = International Agency for Research on Cancer
ICP-OES = inductively coupled plasma-optical emission spectrometryIL-1 = interleukin-1
LDH = lactate dehydrogenase
MDGF = macrophages-derived growth factor
MTT = 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide
NIOSH = National Institute for Occupational Safety and Health
NOAEL = no observed adverse effect level
OECD = Organization for Economic Co-operation and Development
OSHA = Occupational Safety and Health Administration
OTC = over-the-counter
Panel = Expert Panel for Cosmetic Ingredient Safety
PEL = permissible exposure limit
PMN = polymorphonuclear
REL = recommended exposure limit
t50=50% decrease of tissue viability
TG = test guideline
UDS = unscheduled DNA synthesis
UV = ultraviolet
VCRP = Voluntary Cosmetic Registration Program
wINCI Dictionary = web-based International Cosmetic Ingredient Dictionary and Handbook

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DRAFT ABSTRACT
The Expert Panel for Cosmetic Safety (Panel) assessed the safety of naturally-sourced clay ingredients as used incosmetic formulations. All of these ingredients are reported to function in cosmetics as absorbents and bulking agents; othercosmetic functions are also reported. The Panel reviewed all relevant data and concluded that…(to be determined).
INTRODUCTION
The Expert Panel for Cosmetic Ingredient Safety (Panel) previously reviewed the safety of 6 naturally-sourced clay
ingredients in a report that was published in 2003.1 At that time, the Panel concluded that these ingredients are safe as usedin cosmetic products. In accordance with its Procedures, the Panel evaluates the conclusions of previously-issued reports
approximately every 15 years, and it has been at least 15 years since this assessment has been issued. This report has beenreopened to reassess the safety of the 6 clays included in that original report, and also includes one additional ingredient, i.e.,
Clay. In total, this report assesses the safety of 7 naturally-sourced clay ingredients (listed below) as used in cosmetics.
According to the web-based International Cosmetic Ingredient Dictionary and Handbook (wINCI; Dictionary; see Table 1),
all of these ingredients are reported to function in cosmetics as absorbents and bulking agents; other cosmetic functions arealso reported. 2
Attapulgite*
Bentonite*
Clay
Fuller’s Earth**Previously reviewed by the Panel.

Hectorite*
Kaolin*Montmorillonite*

The Panel has also reviewed related ingredients. In a report that was finalized in 2019, the Panel concluded thatsynthetically-manufactured amorphous silica and hydrated silica are safe in the present practices of use and concentration
when formulated to be non-irritating.3 In 2021, the Panel concluded that silicate ingredients, including aluminum silicate andmagnesium aluminum silicate, are safe in cosmetics in the present practices of use and concentration when formulated to be
non-irritating, with the exception that the data are insufficient to make a determination that naturally-sourced (i.e., mined)
silicate ingredients are safe for use in products that may be incidentally inhaled.4 (The reports on these ingredients areavailable on the Cosmetic Ingredient Review (CIR) website (https://www.cir-safety.org/ingredients). Although the clay
ingredients are comprised of silica and/or silicates, silicates, synthetically-manufactured amorphous silica, and hydrated silica
are neither part of this safety assessment, nor are data from those reports included in this assessment.
This safety assessment includes relevant published and unpublished data that are available for each endpoint that isevaluated. Published data are identified by conducting an exhaustive search of the world’s literature. A listing of the searchengines and websites that are used and the sources that are typically explored, as well as the endpoints that the Panel typicallyevaluates, is provided on the CIR website (https://www.cir-safety.org/supplementaldoc/preliminary-search-engines-andwebsites; https://www.cir-safety.org/supplementaldoc/cir-report-format-outline). Unpublished data are provided by thecosmetics industry, as well as by other interested parties.
Excerpts from the summaries of the previous report on clay ingredients are disseminated throughout the text of this rereview document, as appropriate, and are identified by italicized text. (This information is not included in the tables or thesummary section.)
CHEMISTRY
Definition
The definitions of Clay (CAS No. 53801-44-8) and the other clay ingredients included in this review are provided inTable 1.2 These inorganic oxide ingredients, comprising in part silicon dioxide, are solids derived from naturally occurring
minerals.
Structure
Clays in general have atomic lattices consisting of two structural units. One unit consists of two sheets of closely packed
oxygens or hydroxyls. Aluminum, iron, or magnesium atoms are embedded within these sheets in octahedral coordination,
so that they are equidistant from the oxygen or hydroxyl groups. The second unit is composed of silica tetrahedrons.
Assuming there are no distortions in each tetrahedron, a silicon atom is equidistant from four oxygens or hydroxyls, if
needed to balance the structure, arranged in the form of a tetrahedron with a silicon atom in the center. The silica
tetrahedral groups are arranged in a hexagonal network, which is repeated infinitely to form a sheet of composition
Si4O6(OH)4. The tips of the tetrahedrons all point in the same direction and the bases are all in the same plane. Substantial
distortion of these units occurs in order to fit into determined unit-cell dimensions of minerals.
Figure 1 depicts the general structure of clay ingredients. Clays are comprised of magnesium, lithium, aluminum,
and/or iron silicate sheets with various exchangeable cations. These sheet-like structures are in sharp contrast to thehexagonal crystalline structure of crystalline silica (e.g., quartz).

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Figure 1. General structure of clay ingredients.CIR Staff

Attapulgite
The structurally important element is the amphibole double silica chain oriented with its long direction parallel to thec-axis.1 Attapulgite consists of double silica chains situated parallel to the c-axis with the chains linked together throughoxygens at their longitudinal edges. Tetrahedral apexes in successive chains point in the opposite direction. The linked
chains form a kind of double-ribbed sheet with two rows of tetrahedral apexes at alternate intervals in the top and bottom of
the sheets. The ribbed sheets are arranged so that the apex oxygens of successive sheets point together and are held together
by aluminum and/or magnesium in octahedral coordination between the apex oxygens of successive sheets. Chains of watermolecules run parallel to the c- axis and fill the interstices between the amphibole chains. Aluminum substitutions for silicon
are considered probable.
Bentonite, Hectorite, and Montmorillonite
Bentonite, Hectorite, and Montmorillonite (also known as smectites) units comprise of two silica tetrahedral sheets witha central alumina octahedral sheet.1 All tetrahedral tips point in the same direction and toward the center of the unit. The
tips of the tetrahedrons of each silica sheet and one of the hydroxyl layers of the octahedral sheet form a common layer. As in
Kaolin, the atoms common to both the tetrahedral and octahedral layer are O instead of OH. These layers are continuous in
the a and b directions and are stacked one above the other in the c direction. As a consequence, O layers in the units become
adjacent and a very weak bond is created with the possibility of cleavage. The preeminent feature of these clay ingredients isthe ability of water and organic molecules to enter between unit layers and expand in the c direction. Expansion propertiesare reversible; however, the structure is completely collapsed by removal of interlayer polar molecules. Most of these clay
ingredients have substitutions within their lattices: aluminum or phosphorous for silicon in the tetrahedral coordination
and/or magnesium, iron, zinc, nickel, lithium, etc. for aluminum in the octahedral sheet.
KaolinKaolin’s structure is composed of a single silica tetrahedral sheet and a single alumina octahedral sheet combined in aunit so that the tips of the silica tetrahedrons and one of the layers of the octahedral sheet form a common layer.1 All the tipsof the silica tetrahedrons point in the same direction and toward the center of the unit made by the silica and octahedral
sheets. Composite octahedral-tetrahedral layers are formed due to the similarity between the sheets a and b dimensions. The
common layer between the octahedral and tetrahedral groups consists of two-thirds of shared atoms between silicon andaluminum that become O instead of OH. Analyses of Kaolin have shown there is little substitution within the lattice. In asmall percentage of cases, iron and/or titanium has replaced aluminum. This has only been seen in the relatively poor
crystalline varieties of Kaolin.
Chemical Properties
Chemical properties for clay ingredients are described in Table 2.1,5 Clay ingredients are generally described as
insoluble in water.
A supplier has reported the particle size distribution at D50 for Bentonite and Kaolin to be 61.1 µm and 3.1 µm,
respectively.6 The mean particle sizes for 5 different Hectorite products were 19.9 - 25.4 µm, and the particle ranges forthese products were 2.9 - 131.7 µm.7 Another supplier provided specifications for a raw material containing 75% illite, 19%
Kaolin, and 6% Montmorillonite (Table 3); however, there is no information therein to indicate the particle size of resultant
final cosmetic formulations.8

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Attapulgite

Method of Manufacture

Attapulgite is produced through an opencast mining technique, stripping layers with heavy machinery.1 The clay is thentransported to a processing plant where crushing, drying, classification, and pulverizing take place. High-heat drying to
remove water may occur to enhance absorbent qualities. Attapulgite is mined in 10 countries: Australia, China, France,
India, Russia, Senegal, South Africa, Spain, Turkey, and the US.
Bentonite
Large deposits of Bentonite have been discovered in Canada, China, France, Germany, Great Britain, Greece,
Hungary, Italy, Japan, Mexico, New Zealand, North Africa, Poland, South Africa, the post-Soviet states, and the US.1 The
mine ore of Bentonite is processed to remove grit and non-swelling materials.
A supplier has reported that Bentonite is mined mineral.9 The material is then washed, filtered, dried, treated, and tested
for quality.
Kaolin and Montmorillonite
A supplier has reported that a clay product containing 75% illite, 19% Kaolin, and 6% Montmorillonite is naturally
sourced, mechanically refined, and not chemically processed.8 A dehydration process is used to eliminate bacteria prior tosorting through induction.
KaolinDeposits of Kaolin have been found in England, the US, France, the Czech Republic and Slovakia, Germany, andJapan.1 Kaolin is extracted from kaolinized granite by washing it out with powerful water hoses. The clay stream is thenpumped to the separation plant where sand and mica are removed. The purified clay is filtered when wet and then dried.
The very fine powder is formed by milling.
Attapulgite

Composition/Impurities

Attapulgite commonly is found with smectites, amorphous silica, chert, and other minerals.1 A typical mineralcomposition of Attapulgite is approximately 55% silicon dioxide, 10% aluminum oxide, 3.5% iron (III) oxide, 10.5%
magnesium oxide, 0.5% potassium oxide, and 20% water.
Bentonite
The principal constituent of Bentonite is Montmorillonite.1 However, other minerals such as illite, kaolinite, andnonargillaceous detrital minerals can be present. Most bentonites appear relatively pure and other mineral contributions
rarely exceed 10%. Cristobalite is often present. Montmorillonite compositions frequently vary either in its lattice structure
or in the exchangeable ions present. A typical mineral composition of Bentonite is approximately 60% silicon dioxide, 20%
aluminum oxide, 3% iron (II) oxide, 1.5% magnesium oxide, 0.6% calcium oxide, 0.6% potassium oxide, and 21% sodiumoxide.
According to the Food Chemicals Codex, Bentonite is comprised of natural smectite clays consisting primarily of
colloidal hydrated aluminum silicates of the Montmorillonite or Hectorite type of minerals with varying quantities of alkalis,
alkaline earths, and iron.5 Food-grade Bentonite should contain no more than 5 mg/kg arsenic, no more than 15 mg/kg lead,and no more than 1000 colony-forming units (cfu)/g aerobic microbes. Bentonite should be negative for Escherichia coli in
25 g.
In particle size analysis of Bentonite, 90% of the particles were smaller than 68 µm, 50% were smaller than 5µm, and
10% were smaller than 2 µm.10 No particles were smaller than 0.9 µm. A second analysis of Bentonite showed that 90% of
the particles were smaller than 25 µm, 50% were smaller than 6.5 µm, and 10% were smaller than 1.6 µm.11 No particles
were smaller than 0.5 µm.
Fuller’s Earth
Principal deposits of Fuller’s Earth include Montmorillonite, Bentonite, Attapulgite, and sepiolite.1
Hectorite
Principal impurities of Hectorite include calcite, dolomite, silica crystals, and grit.1 A typical mineral composition of
Hectorite is approximately 56% silicon dioxide, 0.1% aluminum oxide, 0.03% iron (III) oxide, 25% magnesium oxide, 0.1%
potassium oxide, 3% sodium oxide, 1% lithium dioxide, 6% fluorine, and 12% water.
According to some suppliers of Hectorite products (97 - 100% pure), crystalline silica (also described as quartz and/or
CAS# 14808-6-7) may be an impurity.12,13 Quantities of crystalline silica were reported to be 1-3%.

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Kaolin and Montmorillonite
A supplier has reported that a clay product containing 75% illite, 19% Kaolin, and 6% Montmorillonite does not contain
quartz.8 Trace heavy metals may be present: < 0.5 ppm antimony, < 17 ppm arsenic, < 0.5 ppm cadmium, < 7 ppm cobalt,< 0.5 ppm tin, < 0.05 ppm mercury, < 20 ppm nickel, and < 20 ppm lead were detected using inductively coupled plasmaoptical emission spectrometry (ICP-OES). Bacterial, yeast, and mold content were below threshold of detection. Dioxin andpolychlorinated biphenyl “results are near zero.”
KaolinQuartz, mica, and feldspar are often found associated with Kaolin as the crude mineral and are often removed throughscreening and elutriation.1 Potentially pathogenic organisms were absent. The bacteria present were mostly gram-positive
aerobic spore-formers. A typical mineral composition of Kaolin (reported as kaolinite) is approximately 45% silicon dioxide,
39% aluminum oxide, 0.8% iron (III) oxide, 0.08% magnesium oxide, 0.08% calcium oxide, 0.1% potassium oxide, 0.7%
sodium oxide, 0.2% titanium (IV) oxide, and 14% water.
According to the Food Chemicals Codex, Kaolin is a purified clay consisting mainly of alumina, silica, and water.5
Food-grade Kaolin should contain no more than 3 mg/kg arsenic and no more than 10 mg/kg lead.
According to some suppliers of Kaolin products (up to 100% pure), crystalline silica (described as quartz, free
respirable silica, and/or CAS # 14808-6-7) may be an impurity.14,15 Quantities of crystalline silica were reported to be < 2%.
Montmorillonite
A typical mineral composition of Montmorillonite is approximately 51% silicon dioxide, 20% aluminum oxide, 0.8%
iron (III) oxide, 3% magnesium oxide, 2% calcium oxide, 0.1% potassium oxide, 0.04% sodium oxide, 0.1% zinc oxide, and
23% water.1
USE
Cosmetic
The safety of the cosmetic ingredients addressed in this assessment is evaluated based on data received from the US
Food and Drug Administration (FDA) and the cosmetics industry on the expected use of these ingredients in cosmetics, anddoes not cover their use in airbrush delivery systems. Data are submitted by the cosmetic industry via the FDA’s Voluntary
Cosmetic Registration Program (VCRP) database (frequency of use) and in response to a survey conducted by the Personal
Care Products Council (Council) (maximum use concentrations). The data are provided by cosmetic product categories,
based on 21CFR Part 720. For most cosmetic product categories, 21CFR Part 720 does not indicate type of application and,
therefore, airbrush application is not considered. Airbrush delivery systems are within the purview of the US Consumer
Product Safety Commission (CPSC), while ingredients, as used in airbrush delivery systems, are within the jurisdiction of the
FDA. Airbrush delivery system use for cosmetic application has not been evaluated by the CPSC, nor has the use ofcosmetic ingredients in airbrush technology been evaluated by the FDA. Moreover, no consumer habits and practices data or
particle size data are publicly available to evaluate the exposure associated with this use type, thereby preempting the ability
to evaluate risk or safety.
According to 2022 VCRP survey data, Kaolin has the most reported uses in cosmetic products, with a total of 1046; themajority of uses are in leave-on formulations (Table 4).16 Bentonite has the second most reported uses in cosmetic products,
with a total of 262; a little more than half are reported in leave-on formulations. The frequencies of use for both of these
ingredients have greatly changed since the original safety assessment was finalized; in 1998, Kaolin was reported to have 509
uses, and Bentonite was reported to have 94.1 The results of concentration of use surveys conducted by the Council in 2022
indicate Kaolin also has the highest concentration of use in a leave-on formulation; it is used at up to 53.2% in manicuring
preparations.17 Bentonite is reported to have a maximum concentration of use for leave-on products of 8% in skin care
preparations. According to the original safety assessment, the maximum leave-on use concentration in 1999 for Kaolin was
100% in skin care preparations; the maximum leave-on use concentration for Bentonite was 8% in makeup foundations.1
Clay ingredients may be used in products that can be incidentally ingested; for example, Kaolin is used in lipstick (at up
to 14.5%).17 Additionally, clay ingredients have been reported to be used in products that may come into contact with theeyes and mucous membranes; for example, Kaolin is used in several types of eye makeup preparations (at up to 8.5% ineyeshadows) and in personal cleanliness preparations (at up to 5% in bath soaps and detergents).
Moreover, clay ingredients are used in cosmetic formulations that could possibly be inhaled; for example, Bentonite isreported to be used at 0.9% in spray suntan products and Kaolin is reported to be used at up to 15% in face powders.17 In
practice, as stated in the Panel’s respiratory exposure resource document (https://www.cir-safety.org/cir-findings), most
droplets/particles incidentally inhaled from cosmetic sprays would be deposited in the nasopharyngeal and tracheobronchialregions of the respiratory tract and would not be respirable (i.e., they would not enter the lungs) to any appreciable amount.
Conservative estimates of inhalation exposures to respirable particles during the use of loose powder cosmetic products are
400-fold to 1000-fold less than protective regulatory and guidance limits for inert airborne respirable particles in theworkplace.

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While no data have been submitted from the cosmetics industry indicating that these clay ingredients are used in
nanoform in cosmetic formulation, a report from a nanotechnology research company provides statistical data showing thatnanoclays can be used as cosmetic additives for lipsticks, eyeliners, and toothpaste, functioning for rheology modification,
viscosity control, thixotropic effect, as well as increased stability and pigment dispersibility.18
Although products containing some of these ingredients may be marketed for use with airbrush delivery systems, thisinformation is not available from the VCRP or the Council survey. Without information regarding the frequency andconcentrations of use of these ingredients, and without consumer habits and practices data or particle size data related to thisuse technology, the data are insufficient to evaluate the exposure resulting from cosmetics applied via airbrush delivery
systems.
In regulations regarding cosmetic products in the European Union (EU), no restrictions were listed for Attapulgite,
Clay, Fuller’s Earth, Hectorite, or Montmorillonite.19 Bentonite and Kaolin are listed in Annex IV-Allowed Colorants under
CI 77004 with the chemical name of “natural hydrated aluminum silicate…containing calcium, magnesium or iron carbonate,ferric hydroxide, quartz-sand, mica, etc. as impurities”; the remaining clay ingredients named in this report are not restrictedfrom cosmetic use in any way. Note, these ingredients are not approved as colorants in the US.2 Bentonite, Hectorite, andKaolin were included in the scientific opinion by the EU Scientific Committee on Consumer Safety (SCCS) on the safety ofaluminum in cosmetic products.20 The SCCS concluded that the use of aluminum compounds is safe at the following
equivalent aluminum concentrations up to 6.25% in non-spray deodorants/antiperspirants, 10.60% in spraydeodorants/antiperspirants, 2.65% in toothpaste, and 14% in lipstick.
According to the Australian Industrial Chemicals Introduction Scheme (AICIS), the following ingredients are Tier I
chemicals (not considered to pose an unreasonable risk to the health of workers and public health): Bentonite, Fuller’s Earth,Kaolin, and Montmorillonite.21 Attapulgite is a Tier II chemical (requires risk management measures to be instituted for safeuse for human health). Hectorite is listed as a chemical unlikely to require further regulation to manage risks to humanhealth.
Non-Cosmetic
Based on the properties of broad surface area, rich porosity, diverse morphology, good adsorption performance, andhigh ion exchange capacity, nanoclays have been widely applied in many fields, such as drug delivery systems,22 food andbeverage packaging,23 paper manufacturing,24 and constructional material.25
Attapulgite
Attapulgite is reported to be used in absorbents, pesticides, oil and petroleum treatment, and as a filler in many
products.1
Attapulgite (activated) is used in antidiarrheal drugs (21 CFR§310.545). The data are currently inadequate to establish
general recognition of the safety of effectiveness of this ingredient for this specified use.
Bentonite
Bentonite is reported to be used in foundry sand bonding, bleaching clay in oil refining and decolorizers, filtering
agents, water impedance, animal feed, pharmaceuticals, paint, plasticity increasers, and iron-ore pelletizing.1
Bentonite is generally recognized as safe (GRAS) as a direct food additive for humans (21 CFR§184.1155) and animals(21 CFR§582.1155). Bentonite is also GRAS as an indirect food additive in adhesives and components of coatings (21CFR§175.105), in paper and paperboard components (as a colorant only, 21 CFR§176.170), in adjuvants as a colorant forpolymers (21 CFR§178.3297),
Clay
Clay (natural) is GRAS as an indirect food additive in polymers (cellophane; 21 CFR§177.1200).
Fuller’s Earth
Fuller’s Earth is reported to be used as a military decontaminant for removal of hazardous materials from the skin.26
Hectorite
Hectorite has been approved for use in internally and externally applied products, as well as dentifrices and externallyapproved pharmaceuticals.1
Hectorite is used as a digestive aid and an external analgesic for insect bites, stings, and poison ivy, sumac, and oak (21CFR§310.545); however, the data are currently inadequate to establish general recognition of the safety of effectiveness of
this ingredient for these specified uses. Hectorite is also reported to be used as drug-delivery system in anticancer therapy
because of its biocompatibility, mechanical strength, and natural availability.27

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KaolinKaolin is reported to be used in the paper industry to fill and coat the surface of paper, as a filler in rubber andplastics, paint extender, ceramics manufacture, ink, adhesives, insecticides, medicines, food additives, bleaching, adsorbents,
cement, fertilizers, crayons, pencils, detergents, porcelain enamels, paste, foundries, linoleum, floor tiles, and textiles.1 It has
been classified by the National Formulary as a tablet and/or capsule diluent.
Kaolin clay is GRAS as an indirect food additive with no limitation other than current good manufacturing practice (21CFR§186.1256). It is used in the manufacture of paper and paperboard that contact food. Kaolin (colloidal) is an approved
over-the-counter (OTC) drug as an antidiarrheal active ingredient (21 CFR§335.10), an anorectal active ingredient (21CFR§346.14), and a skin protectant active ingredient (from 4% to 20%; 21 CFR§347.10). Kaolin is used as a digestive aid(21 CFR§310.545); however, the data are currently inadequate to establish general recognition of the safety of effectivenessof this ingredient for this specified use. Kaolin is exempted from the requirement of a tolerance for pesticide residues whenused on or in food commodities to aid in the control of insects, fungi, and bacteria (food/feed use; 40 CFR§180.1180).
Montmorillonite
Montmorillonite is reported to be used for food packaging and in paper manufacturing.23,24

KaolinTOXICOKINETIC STUDIES
Absorption, Distribution, Metabolism, Excretion (ADME)

In a dietary study, a group of 10 male Sprague-Dawley rats were fed a control diet plus 0.5 ml 20% Kaolin – 1% pectinfor 48 h.1 Stool samples were collected 72 h late and analyzed for volume, sodium, potassium, and fat content. The results
were a 103% increase in sodium, a 184% increase in potassium, and fat excretion remained at baseline.
Montmorillonite
Polydisperse and monodisperse [134Cs]-labeled Montmorillonite suspensions were administered to groups of 40 rats
and mice and to 120 beagle dogs by a multiport nose-only inhalation exposure system.1 Aerosol concentrations ranged from
0.1 to 0.001 mg of fused Montmorillonite/l of air. Equal numbers of male and female rats and mice and 74 male and 46
female dogs were utilized. Exposure times for rats and mice ranged from 25 to 45 min and for dogs 15 to 50 min. All
animals were whole-body counted for the labeled particles. Rats and mice were counted on exposure days 2, 4, 8, 16, 32, 64,
128, 256, 365, 512, 730, and 850 and the dogs were also counted on the same schedule, but also at 4, 5, 7, and 9 yr after
inhalation exposure. Excreta collections were made for animals from each exposure group. Five rats and 5 mice from eachgroup were killed 4 h after exposure. The remaining rats and mice were killed at various times after exposure. Two dogs
were scheduled for termination at times ranging from 4 h to 9 yr. All animals were necropsied and tissues from lungs, lungassociated lymph nodes, gastrointestinal tract, spleen, kidneys, abdominal lymph nodes, blood, skeleton, muscle, and skinwere prepared for analysis of [134Cs]-exposure. The mass of material deposited into the lungs of rats and mice was ~0.01 to
0.1 mg and for dogs was ~1 to 10 mg. The mass of Montmorillonite for all three species was < 0.1 mg/g of lung. Clearanceof the initial 134Cs occurred by dissolution and mechanical clearance. Mechanical clearance from the nasopharynx was
rapid, and the clearance rate was decreased to a negligible value for all three species within a few days. Most initial deposit
cleared via the gastrointestinal tract. Long-term mechanical clearance from the pulmonary region occurred at a constantrate for all species. Solubilization was the primary factor in long-term lung clearance for most particles inhaled by dogs andmechanical clearance was dominant in rats and mice. Most of the long-term clearance of deposited particles went to lungassociated lymph nodes in dogs and occurred at a slower rate as compared to rats and mice. Rats and mice had a rapid
clearance from the pulmonary region, where most of the mechanical clearance occurred via the gastrointestinal tract. Longterm clearance of the particles in dogs occurred at 3500-d half-time in the lymph nodes and 6900-d half-time clearance inthe gastrointestinal tract. The transport rate of the particles in the dog was 0.0002/d of the lung burden. The long-term
biological clearance half-term day was 690 d for rats and 490 d for mice. The lymph node accumulation process wasmodeled by a short-term process that became negligible after a few days.
Radiolabeled, [134Cs]-fused Montmorillonite particles were instilled into specific lung lobes or injected
intraperitoneally into 32 beagle dogs.1 Necropsy was performed 34, 182, and 365 d later. Specific sites of instillation
included right apical lobe, right cardiac lobe, right diaphragmatic lobe, right intermediate lobe, left apical lobe, left
diaphragmatic lobe, and intraperitoneal. Initial burdens in the peritoneal cavity or the lungs ranged from 0.50 to 14 µCi of[134Cs] for 29 dogs and from 42 to 64 µCi of [134Cs] for lung burdens for the other 3 dogs. Effective translocation half-timeof lung instillations was 390 d. The accumulation rate of [134Cs]-labeled particles in the lymph nodes was 0.03% per day.
Individual lung lobes cleared particles to 1 - 2 lymph nodes, and specific lymph nodes accumulated particles from 1 - 3 lung
lobes. Lymph nodes that collected particles from the lung included the left mediastinal node and the left, left-middle, right,
and right-middle tracheobronchial lymph nodes. The destination for translocated particles was primarily the nodes
proximate to the tracheal bifurcation. Particles injected into the peritoneal cavity were translocated mainly to mesentericDistributed for Comment Only -- Do Not Cite or Quote

lymph nodes and left and right sternal lymph nodes. A small percentage of particles went to the left tracheobronchial lymph
node.
Kaolin and Montmorillonite
In ex vitro bioavailability studies using human skin models, the ability of transcutaneous passage of heavy metals(vanadium, lead, arsenic, barium, nickel, chromium, and aluminum) in 3 clay pastes was analyzed.28 The clays pastes werewhite Montmorillonite, Kaolin, and a clay product containing 75% illite, 19% Kaolin, and 6% Montmorillonite.
Approximately 150 g of each product were tested with human skin samples in Franz cells and incubated for 24 h. The tested
products, the diffusion liquids, and the storage liquids were then analyzed for metals content (details not provided). No
detectable quantities of heavy metals were found in the diffusion or storage liquids. It was determined that the heavy metal
traces in the clay pastes did not penetrate cutaneous tissue.

DermalKaolin and Montmorillonite

TOXICOLOGICAL STUDIES
Acute Toxicity Studies

In an acute dermal toxicity study performed in accordance with Organization for Economic Co-operation andDevelopment (OECD) test guideline (TG) 402, rats received 2000 mg/kg bw of a clay product containing 75% illite, 19%
Kaolin, and 6% Montmorillonite on clipped skin.28 The test material was moistened with 0.2 ml distilled water. A control
group received only distilled water. The rats were observed for 14 d. No mortality or clinical signs of toxicity wereobserved. The LD50 was greater than 2000 mg/kg. No further details were provided.
Oral
Hectorite
Five male and 5 female Sprague-Dawley rats were administered a single dose of 5 g/kg of Hectorite by gavage.1 Noneof the animals died; the acute oral LD50 was > 5.0 g/kg bw.
KaolinIn an acute oral study, 120 rats were fed doses of Kaolin ranging from 100 to 210 g/kg.1 Fourteen rats were controls.
Kaolin was inert and non-static except for the danger of bowel obstruction resulting in perforation. The clinical signs werelistlessness, anorexia, oliguria, hypothermia, and dyspnea. These were a pathological reaction from overdistention of thealimentary canal by an inert solid. The number of fatalities and the incidence and advance of bowel obstruction along thesmall intestine were dose-related. The dose that killed 50% of the rats by bowel obstruction was 149 g/kg.
Kaolin and Montmorillonite
In an acute oral study performed in accordance with OECD TG 423, rats were exposed to a single dose of 2000 mg/kg
bw of a clay product containing 75% illite, 19% Kaolin, and 6% Montmorillonite in distilled water.28 No mortality or clinicalsigns of toxicity were observed. Visceral examination did not reveal any lesions of pathological significance except uterine
distension in one rat, which was not considered to be treatment-related. The LD50 was greater than 2000 mg/kg bw. No
further details were provided.
Inhalation
Kaolin and Montmorillonite
In an acute inhalation study performed in accordance with OECD TG 403, rats were exposed to 3.856 mg/l air of a clay
product containing 75% illite, 19% Kaolin, and 6% Montmorillonite.28 A control group was exposed to air passed throughinert bed material (iron grit). Both groups of rats were exposed for 4 h and then observed for 14 d. No mortality or clinicalsigns of toxicity were observed. The LC50 was greater than 3.856 mg/l. No further details were provided.
Oral
Montmorillonite

Subchronic Toxicity Studies

In a 90-d oral study, 10 male Wistar rats received a modified Montmorillonite clay (40 mg/kg/d) in the diet.29 Another10 male rats received only standard diet as control. During the treatment period, clinical signs, body weight, and feed andwater consumption were recorded weekly. At the end of the treatment period, the rats were fasted for 18 h before being
killed. Histopathological examinations were performed, and liver, kidneys, lungs, spleen, brain, testes, gastrointestinal tract,and heart were weighed. Blood samples were obtained for analysis. No rats died during the treatment period and noremarkable clinical signs were observed. Body weight gains and feed and water consumption were comparable to controls.
No significant changes were noted in clinical biochemistry, organ weights, or in the histopathological examinations whencompared to controls.

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Parenteral
KaolinToxicity of some of the minerals present in coal-mine dust was examined in groups of 10 SPF Sprague-Dawley rats.1
The rats were exposed over a period of 3 mo to 50 mg/animal intratracheal instillations of Kaolin. The following
assessments were made: weight of the fresh lungs; macroscopic and microscopic lesions in the lungs; amount of collagenand dust present in the lungs; and calculation of the toxicity index from the amount of collagen formed per mg of dust. The
weight of fresh lungs subjected to Kaolin was 1.76 g. Collagen formed per lung was 23.9 mg. The dust per lung was 30.2
mg and the collagen/dust ratio was 0.79. Microscopic examinations of the lungs showed no alveolar proteinosis but Kaolin
was detected in the bronchovascular lymphoid sheaths. No information regarding nonexposed lungs was presented. The
opinion of the investigators was that exposure to Kaolin results in “pulmonary toxicity” and possesses “fibrogenic
capacity.”
Oral
Montmorillonite

Chronic Toxicity Studies

The potential toxicity of a naturally-occurring calcium Montmorillonite clay was studied using groups of 10 male and
10 female Sprague-Dawley rats for 28 wk.30 The rats received the test material at 0, 0.25, 0.5, 1.0, or 2.0% w/w in their feed.
Rats were observed daily for clinical signs and deaths. Feed consumption was recorded daily for the first month and thenevery fourth day. Body weights were measured weekly. At the treatment end, final body weights were recorded and blood
was drawn for analysis. After the rats were killed, histopathological examinations were performed, and select organs were
weighed. Total feed consumption, cumulative feed consumption, body weight, total body weight gain, and relative organ
weights were not affected in either sex at any dose tested. No differences in relative organ weights or gross or
histopathological changes compared to controls were observed. Non-dose-dependent significant changes were observed inmean corpuscular hemoglobin, serum calcium, serum vitamin A, and serum iron.
DEVELOPMENTAL AND REPRODUCTIVE TOXICITY (DART) STUDIES
KaolinGroups of 12 Sprague-Dawley female rats were fed a control diet, 20% Kaolin diet, or iron-supplemented 20% Kaolin
diet.1 The diets were fed for 37 to 86 d, 69 to 85 d, and 96 to 117 d prior to fertilization. These same diets were fed for theduration of the gestation period. The animals fed the 20% Kaolin diet had significant reductions in hemoglobin, hematocrit,and red blood cell numbers, indicating maternal anemia. Significant reduction in the birth weight of the pups was observed.
Animals fed the iron-supplemented diet maintained their hematocrit, hemoglobin, and red blood cell levels.
In a study of 12 fetal lambs and 6 fetal rhesus monkeys, sterile suspensions of 2% Kaolin in saline were injected into thecisterna magna.1 Fetal lambs received 1 to 3 ml of Kaolin and fetal monkeys received 0.5 to 1.0 ml of Kaolin. After injection,
the fetuses were replaced into the uterus. Prenatal ultrasound monitoring was used to document the progression of fetal
ventriculomegaly. Cesarean sections were scheduled for gestation days 140 to 145 for the sheep and gestation days 160 to
165 for the monkeys. Newborn animals with gross head enlargement were killed 2 h after birth and necropsy was performed.
Brains were sectioned for gross and microscopic examination. Five lambs and 1 monkey underwent ventriculoamniotic
shunting at 120 d after gestation. Ventricular dilatation was apparent at 1 wk following Kaolin injections. The cerebral
mantle was markedly thinned, with relative preservation of the cortex and severe attenuation of the white matter. The
average cortical thickness of the cingulate gyrus in the Kaolin-injected sheep was 716 µm compared to 1225 µ in control
animals. The corpus callosum was an average of 125 µm in thickness in the sheep compared to 475 µm in control animals.
Microscopic examination found the cortical neurons well preserved and contained the complexity and density of neuralprocesses. A mild-to-moderate fibrotic reaction and inflammatory cell response along the basal meninges was apparent. A
large number of macrophages containing Kaolin infiltrated the subarachnoid space. In 5 fetuses, Kaolin was injected
mistakenly into either the epidural tissues superficial to the cisterna magna or into the cervical musculature. None of thesefetuses had hydrocephalus at birth.
GENOTOXICITY STUDIES
Attapulgite
In 2 studies looking at unscheduled DNA synthesis (UDS) in rat hepatocytes, Attapulgite did not cause a significant
increase in DNA-specific activity at up to 10 µg/ml with no cytotoxicity.1 However, in another UDS study using rat pleural
mesothelial cells, Attapulgite tested at 2, 4, or 10 µg/cm2 produced a significant increase in UDS and inhibited cell growth at
10 µg/cm2. Attapulgite did not induce point mutations in a third DNA study.

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Hectorite
In the Salmonella typhimurium LT2 spot test (TA98, TA100, TA1535, TA1537, and TA1538) with or without metabolic
activation, Hectorite was found to be non-mutagenic.1 In primary hepatocyte cultures, the addition of Attapulgite at 10µg/cm2 caused significant increases in UDS in rat pleural mesothelial cells.
In vitro and in vivo genotoxicity studies summarized here are described in Table 5. A clay product containing 75%
illite, 19% Kaolin, and 6% Montmorillonite (5000 µg) was not mutagenic in an Ames test, with or without metabolic
activation.28 Unmodified Montmorillonite clay (at up to 125 µg/ml) and one type of cation-exchanged (hexadecyltrimethylammonium) montmorillonite clay (at up to 250 µg/ml) also were not mutagenic in an Ames test with or without metabolic
activation, but significant increases in revertant colonies were observed in one strain with metabolic activation in 2 othercation-exchanged montmorillonite clays.31 No mutagenic activity was observed in a Salmonella/microsome assay with andwithout metabolic activation when tested in Montmorillonite and cation-exchanged montmorillonite in both nano- and nonnano-sized material at up to 141 µg/ml and up to 14.1 µg/plate, respectively.32 However, the cation-exchanged
montmorillonite material (both nano- and non-nano-sized, at up to 226 µg/ml and 170 µg/ml, respectively) in this study was
genotoxic in a concentration-related manner in a Comet assay with Caco-2 cells. The natural clay was not consideredgenotoxic. A clay product containing 75% illite, 19% Kaolin, and 6% Montmorillonite did not induce chromosomal
aberrations in Chinese hamster ovary (CHO) cell cultures when tested at up to 5000 µg/ml, with or without metabolic
activation.28 Statistically significant increases in the frequency of micronuclei were induced by Montmorillonite clay at 62.5µg/ml in a cytokinesis block micronucleus cytome assay in human hepatoma cell lines, but this effect was not observed at aconcentration of 31.25 µg/ml or lower.33 No effects in nucleoplastic bridges or nuclear buds were observed at any
concentration in this study. In an in vitro micronucleus assay and kinetochore analysis using human lung fibroblasts, thegenotoxic potential of Bentonite at up to 15 µg/cm2 was determined to be generally low, but could be altered by the content
of quartz and available transition metals.34
In an in vivo Comet assay, rats were given 2 oral doses of up to 1000 mg/kg bw cation-exchanged montmorillonite
clay.35 There was no statistically significant difference in % tail DNA between the negative controls and the different
treatment groups for any of the cells (liver, kidneys, colon) tested.
CARCINOGENICITY STUDIESThe International Agency for Research on Cancer (IARC) has determined there is inadequate evidence in humans forthe carcinogenicity of Attapulgite (IARC uses the mineralogical term “palygorskite” for Attapulgite).36 Further, IARC hasdetermined there is insufficient evidence in experimental animals for the carcinogenicity of short Attapulgite fibers (< 5 µm);
however, there is sufficient evidence in experimental animals for the carcinogenicity of long Attapulgite fibers (> 5 µm).
Overall, long Attapulgite fibers (> 5 µm) are possibly carcinogenic to humans (Group 2B) and short Attapulgite fibers (< 5µm) cannot be classified as to their carcinogenicity to humans (Group 3).
Attapulgite (palygorskite fibers > 5 µm in length) is listed by California Proposition 65 as a carcinogen.37
Inhalation
Attapulgite
In a rat inhalation study, groups of 40 (20 male and 20 female) SPF Fischer rats were exposed to samples ofAttapulgite dust mined in Lebrija or Leichester in inhalation chambers at a concentration of 10 mg/m3 for 6 h/d for 5 d/wk
until they were killed.1 Negative and positive control groups received Kaolin and crocidolite, respectively, at 10 mg/m3. Fouranimals were killed at 3, 6, and 12 mo, and the remaining rats were allowed to live their life span. All animals were subject
to necropsy; the lungs, liver, spleen, kidneys, and other relevant organs were examined microscopically. At microscopic
examination, 1 peritoneal mesothelioma, 1 adenocarcinoma, and 3 bronchoalveolar hyperplasia were found in rats treatedwith Lebrija Attapulgite. Thirty-five rats had no proliferative changes. In rats treated with Leichester Attapulgite,
proliferative lesions observed included 2 mesothelioma, 1 peritoneal mesothelioma, 1 malignant alveolar neoplasm, 2 benign
alveolar neoplasms, and 8 bronchoalveolar hyperplasias. Twenty-seven rats had no proliferative lesions. Rats exposed to thenegative-control Kaolin had 2 bronchoalveolar tumors. Rats in the positive-control crocidolite group had 1 adenocarcinoma
and 3 bronchoalveolar tumors.
KaolinKaolin was reported to be the negative control in the above rat inhalation study.1 The rats received 10 mg/m3 Kaolinfor 6 h/d for 5 d/wk. Two bronchoalveolar tumors were reported.
Parenteral
Attapulgite
In an intratracheal study, groups of 5 rats received a single instillation of Attapulgite at 1, 5, and 10 mg.1 One monthafter treatment, bronchoalveolar lavage and microscopic examination of the lungs were performed. The average length of
the fibers was 0.8 µm, and 100% of the fibers were less than 3 µm. Every test animal had type A lesions, which are

Distributed for Comment Only -- Do Not Cite or Quotecharacterized by an accumulation of inflammatory cells, mostly macrophages, and epithelioid cells around fiber deposits.
These inflammatory cells form a compact cellular infiltrate at the periphery of the deposits and some are focally dispersed
throughout the alveolar region. The bronchoalveolar lavage (BAL) had mostly macrophages and a small number ofneutrophils at 5- and 10-mg doses. At the 5-mg dose, 3.6% of the cells were lymphocytes.
Two groups of 30 to 50 female Osbourne-Mendel rats received a single direct application to the left pleural surface by
open thoracotomy of 40 mg of 1 of 2 Attapulgite samples.1 The samples were 90% pure with quartz being the othercomponent. One dose consisted of fibers > 4 µm and the other contained no fibers > 4 µm. The rats were killed at the end of
2 yr. Pleural sarcomas were seen in 2/29 rats. The incidences of pleural sarcomas in the untreated groups were 3/491 and17/615 of the rats receiving the pleural implants of Attapulgite. Of rats receiving the positive control, crocidolite, 14/29
developed pleural mesotheliomas.
Attapulgite (20 mg/ml of 0.9% sodium chloride) was injected into the pleural cavities of 36 Sprague-Dawley rats.1 The
median fiber length was 0.77 µm. Two control groups, untreated and saline-injected, were utilized. Necropsy was
performed after the rats died or killed when moribund. No mesothelial neoplasms were found in either controls or in rats
treated with Attapulgite. Survival times between the Attapulgite-treated group and the controls were not statisticallydifferent.
Attapulgite was injected intrapleurally as a single dose of 0.5, 2, 4, 8, 16, or 32 mg into 6 groups of 25 Fischer 344
rats.1 Nearly all the fibers were <1 µm in length. Mesotheliomas were present in 2/140 treated rats compared to 1/79
incidences in control groups. The median life span was 839 days for Attapulgite-treated animals and 729 days for
nontreated animals.
In another intrapleural study, injections of 20 mg of different Attapulgite fiber samples in 1 ml of saline were given to 2mo-old Sprague-Dawley rats.1 The control group received only a saline injection. All rats were allowed to live full life span.
The mean length of Attapulgite fibers in this experiment was 0.77 µm. The number of groups were not reported; however, 36
rats were reported to comprise each group. Pulmonary and thoracic neoplasms were fixed and processed forhistopathological examination. The survival time of the treated groups (788 ± 155 days) was very similar to that of thecontrol groups (809 ± 110 days). The incidence of mesothelioma was 0% for control groups and treated groups. The
researchers concluded Attapulgite was not carcinogenic in this study.
Samples of Attapulgite from Lebrija, Torrejon, and Leichester were injected intrapleurally as a single injection ingroups of 20 male and 20 female SPF Fischer rats.1 Concentrations were not reported; however, fiber length was reported
as < 2 µm, for Lebrija Attapulgite, at most 0.54% > 6 µm for Torrejon Attapulgite, and 19% > 6 µm for Leichester
Attapulgite. Kaolin and saline were used as negative controls, and crocidolite was used as a positive control. The animals
were allowed to live their life span but were killed if they appeared distressed. Upon death, necropsy and microscopic
examination of tissue were performed. Dust extraction was obtained from granulomas removed from the diaphragm or
mediastinal tissue. Mesotheliomas were reported in 2, 14, 30, and 34 rats for Lebrija Attapulgite, Torrejon Attapulgite,
Leichester Attapulgite, and crocidolite, respectively. In the negative controls, no mesotheliomas were reported for the Kaolin
and 1 mesothelioma was reported for the saline group. Lebrija Attapulgite dust extracted from the lung had fibers < 2 µm.
Material examined from Torrejon Attapulgite was fibrous and had fiber length up to 8 µm. Leichester Attapulgite fibers fromextracted lungs were up to 25 µm. The investigators considered these fibers to be tumorigenic.
Three samples of 25 mg of Attapulgite dust were injected intraperitoneally into 40 Wistar rats.1 Electron microscopy ofthe sample revealed 37.5% of fibers < 2 µm long and 70.0% < 5 µm. All animals were observed until they died either
spontaneously or were killed. Saline was injected into 80 control animals. The time required to produce the first tumor in therats was 257 days and the tumor incidence rate was 65%.
In a carcinogenicity study conducted with 3 samples of Attapulgite labeled Georgia, Lebrija, and Morimoiron, female
Wistar rats (112, 115, and 114 per sample type, respectively) were injected intraperitoneally.1 Each sample was injected
1/wk for 9 wk at 60 mg per injection. Fiber dimensions for each of the samples Morimoiron, Georgia, and Lebrija were as
follows: <50% fiber length was 0.7, 0.5, and 0.8 µm, respectively and <50% fiber diameter of 0.07, 0.07, and 0.04 µm,
respectively. Some rats died spontaneously or others in poor health were killed. Surviving animals were killed 2.5 yr after
treatment for necropsy. At necropsy, neoplasms or organs with suspected neoplasm tissue were fixed for microscopic
examination. The percentage of rats with tumors were 3.5%, 3.5%, and 3.6% for the Morimoiron, Lebrija, and Georgia
samples, respectively. These 3 samples were determined to be noncarcinogenic.
In another experiment by the same investigators, a fourth sample of Attapulgite from Caceres was tested in 30 rats.1
Intraperitoneal injections of 2, 4, and 4 mg were administered consecutively for 3 wk. The fiber length and diameter of thissample were <50% 1.3 and 0.07 µm, respectively. Animals in poor health were killed. Surviving animals were killed 2.5
years after treatment for necropsy. At postmortem examination, parts of neoplasms or organs with suspected neoplasm tissue
were fixed for microscopic examination. Forty percent of the rats had tumors. The results were considered moderate inrelation to the dose.

Distributed for Comment Only -- Do Not Cite or Quote

Montmorillonite
Heat-treated Montmorillonite in doses of 5, 15, and 45 mg was given to groups of 4 Sprague-Dawley rats byintratracheal instillation.1 Following a 3-mo postexposure period, the animals were killed and tissues were subjected tomicroscopic examination. The Montmorillonite particles were mainly restricted to alveoli within and adjacent to alveolar
ducts regardless of dose. Most particles were contained within small to moderate numbers of pulmonary alveolar
macrophages. However, some particles were free in alveoli. Adjacent alveoli septae were mildly thickened. Interstitial
fibrosis was present in all groups. At the 5- and 15-mg doses, fibrosis was mild to moderate, multifocal, and loose, meaning
less collagen. The 45-mg dose produced dense fibrosis. Macrophages contained clay particles and lymphocytes were present
in the lesions. Occasionally giant multinucleate cells were seen.
OTHER RELEVANT STUDIES
Adsorption
Clay ingredients are reported to adsorb various chemicals, molecules, and microorganisms.1 These compounds
include, but are not limited to, strychnine, quinine, atropine, ampicillin, amoxycillin, Agrobacterium radiobacter,
Escherichia coli, Serratia marcescens, Bacillus species, bacterial endotoxins and enterotoxins, and aflatoxins.
Cytotoxicity
Numerous studies with various cell lines on the cytotoxic and hemolytic effects of clay ingredients have been reported.1
Results varied and may have been dependent on different factors, including mineral composition of the test materials.
Bentonite

Hemostatic Response

The ability for Bentonite (2/3 weight) and a zeolite (type not specified; 1/3 weight) to act as a hemostatic agent wasstudied in 12 male Sprague-Dawley rats.38 Another 12 rats served as controls. Approximately 8 g of the material wasapplied on wounded skin. Wounds were circular, full-thickness and 2 cm in diameter; skin samples were excised andevaluated stereologically after scarification. On days 12 and 21, 6 rats from the test group and 6 rats from the control groupwere killed. At day 12 termination, reduction in the length density of the blood vessels (31%) and diameter of the large andsmall vessels (38% and 16%, respectively) was observed in the rats that received the test material. At day 21 termination,
volume density of both the dermis and collagen bundles was reduced by 25% in the treated rats when compared to thecontrols. The researchers concluded the hemostatic agent containing Bentonite may cause vasoconstriction and inhibition of
neoangiogenesis.
Attapulgite

Other Parenteral Studies

In an intratracheal study, groups of 5 rats received a single instillation of Attapulgite at 1, 5, and 10 mg.1 One monthafter treatment, BAL and microscopic examination of the lungs were performed. The average length of the fibers was 0.8µm, and 100% of the fibers were less than 3 µm. Every test animal had type A lesions. Type A lesions are characterized byan accumulation of inflammatory cells mostly macrophages, and epithelioid cells around fiber deposits. These inflammatory
cells form a compact cellular infiltrate at the periphery of the deposits and some are focally dispersed throughout thealveolar region. The BAL had mostly macrophages and a small number of neutrophils at 5 and 10 mg doses. At the 5 mg
dose, 3.6% of the cells were lymphocytes.
Groups of 5 male Wistar rats received 1, 5, or 10 mg of Attapulgite by transtracheal injection to examine alveolar
macrophage production of interleukin-1 (IL-1) and macrophages-derived growth factor (MDGF) from fibroblasts.1 Saline
and chrysotile B asbestos were used as controls. At 1 mo, Attapulgite produced granulomas and the chrysotile B produced
fibrosis. At 8 mo, the granulomatous reactions had either resolved or were greatly diminished, whereas the fibrosis
persisted. Cells obtained by BAL included multinucleated giant macrophages in animals treated with Attapulgite, but not in
those treated with chrysotile B. Enhanced production of IL-1 was seen in all treated groups. MDGF production was only
seen in animals with lung fibrosis.
Attapulgite with a mean fiber length of 0.8 µm and diameter of 0.02 µm was delivered to the lungs of sheep bybronchioscopic cannulation.1 The tracheal lobe of 16 sheep was subjected to a single exposure of 100 mg of Attapulgite in
100 ml of saline. A BAL was conducted at 2, 12, 24, 40, and 60 d, and necropsy was conducted on day 60. Total BAL cells,
macrophages, and neutrophils, fibronectin content, and lactate dehydrogenase (LDH) and β-glucuronidase (β-GLUC)
activity were examined. Nine samples of the tracheal lobe of the lung were obtained each time for microscopic examination.
The controls were saline-exposed sheep and had no changes in BAL or pulmonary morphology. The total BAL cells/ml andsubpopulations increased significantly above control numbers at days 12, 24, and 40 but returned to control levels by day 60.
Albumin and procollagen III did not differ from controls, whereas fibronectin, LDH, and β-GLUC activities weresignificantly above the controls. Microscopic examination revealed infiltrates that were predominantly alveolar andperibronchial lesions. Macrophagic alveolitis with minimal airway distortion was seen. Three sheep had lesions ofperibronchiolar alveolitis.

Distributed for Comment Only -- Do Not Cite or Quote

Bentonite
The ability of Bentonite to increase susceptibility to bacterial pneumonia was studied in mice.1 The animals were
injected intratracheally with 1, 10, or 100 µg Bentonite. In vivo bacterial-infectivity screening assays were conducted byexposing the animals to aerosolized Group C Streptococcus species. The severity of infection was calculated by recording
the deaths of the mice over a 15-d period. Control animals were exposed to titanium dioxide. At the 100 µg dose, Bentonite
increased the infectivity of the bacteria. Mortality was 85%. Even at 10 µg, Bentonite caused increased animal mortality(43.3%). Control dusts at 100 µg produced only a 5% mortality.
The effects of Bentonite dust in rats was analyzed in a 2-part intratracheal study.1 A 0.5 mg dose of Bentonite with amean size of 0.3 µm was instilled. Control animals were injected with sterile saline and titanium dioxide. Animals were
killed at 1, 2, 6, 24, and 48 h and 4 and 7 d after instillation. Bronchopulmonary lavage was carried out and alveolar
macrophages and polymorphonuclear leukocytes were recovered. The activity of LDH and protein content of the lavage
fluid were also determined. In the first experiment, a rapid influx of polymorphonuclear (PMN) leukocytes was detected at 6h. PMN leukocyte response peaked at approximately 19 x 106 cells after instillation and started declining more slowly up to
4 d. At 7 d, the polymorphonuclear leukocyte numbers were 2.5 x 106. The greatest increase in the numbers of alveolar
macrophages recovered occurred at 4 and 7 d. The mean diameter of macrophages increased from 11.0 to 12.5 µm over the
first 48 h after instillation. The mean diameter decreased at 4 and 7 d. LDH activity at 24 h was maintained at 40 mU/ml
and then increased (73 mU/ml) with the influx of polymorphonuclear leukocytes into the lungs after 48 h. Protein
concentration was calculated at 500 µg/cm3 for the first 24 h and was maintained for 48 h.
In the second experiment, after instillation of 5 mg of Bentonite, the animals were killed at 1, 7, 49, and 100 d.1 In
addition to the above measured parameters, peroxidase and lysozyme activity were also measured. A large number ofpolymorphonuclear leukocytes were recovered at day 1. However, the severity of the response did not differ significantly
from the 0.5 mg dose. By 7 d, the numbers had decreased and was similar to control values. A significant decrease in thenumber of alveolar macrophages compared to controls was observed at 24 h after instillation. This decrease was followed
by a sharp increase that exceeded control values by 7 d. Total number estimates were similar to those of the first experiment.
LDH activity and protein concentration from Bentonite and titanium dioxide were very similar. The initial rise at day 1
following administration was short-lived. Peroxidase activity was minimal. Lysozyme activity rose sharply between 1 and 7d, but returned to control values at 49 and 100 d.
In an intratracheal study, a single dose of 40 mg of Bentonite suspended in 1 ml of physiological saline containing
40,000 IU of crystalline penicillin was administered to male CFY rats.1 The Bentonite composition consisted of 73%
Montmorillonite, 18% cristobalite, 3% quartz, 3% feldspar, and 3% other minerals. Particle sizes were < 2 µm. The control
group received 1 ml of physiological saline containing 40,000 IU of crystalline penicillin. Animals were killed 12, 24, 48, or
72 h or 90 d after exposure. Body and lung weight of the rats were measured. The right lung was fixed and sectioned for
microscopic examination. The lipids and phospholipids were analyzed in the left lung. The body weights of the rats weremoderately decreased and the lung weight increased 72 h after Bentonite exposure. After 90 d, the lung weight was only
slightly greater than that of the control animals. Upon microscopic examination at 12 h, Bentonite exposure had resulted ina nonspecific inflammation of mostly neutrophils with perivascular edema, alveolitis, and incipient bronchopneumonia. A
small number of macrophages and lymphocytes were detected. Dust particles were observed in the leukocytes andmacrophages or extracellularly in the alveoli. After 24 h, bronchopneumonia was present after coalescence of theinflammatory foci; the pneumonia then became necrotizing and desquamative. Necrotic neutrophilic leukocytes andeosinophil leukocytes were observed. The reticular network collapsed between 48 and 72 h. After 90 d of exposure,
Bentonite caused storage focal tissue reaction (large foamy cells with pale cytoplasm). Closely-packed cells with darkcytoplasm and nuclei were located at the periphery. After 12 and 24 h, the amount of lipids and phospholipids in the lungs
was not altered. However, between 48 and 72 h, the lipid and phospholipid content increased but distribution remained thesame. After 90 d, the value was the same as seen at 72 h.
In another study by the same research group, male CFY rats were given a single intratracheal dose of 60 mg of
Bentonite in 1 ml of physiological saline containing 40,000 IU crystalline penicillin.1 Bentonite particle size was less than
5 µm. Control groups received 1 ml physiological saline containing 40,000 IU penicillin. Animals were killed at the end of
72 h, weeks 2 and 4, and months 3, 6, and 12. The acid phosphatase activity and the progression of fibrosis were
determined. The lungs were processed for microscopic examination and fibrosis determined by Belt and King’sclassification. Acid phosphatase activity was increased at 72 h and had returned to normal by the first month. Loose
reticulin fibrils, but no collagen, were observed after months 1 - 12.
Bentonite dust was administered intratracheally as a single 60-mg dose to Sprague-Dawley rats.1 The animals were
killed 3, 6, and 12 mo after exposure. The right lung was studied microscopically and the lipids, phospholipids, andhydroxyproline values were determined. Significantly greater phospholipid values compared to controls were observed.
Among the phospholipid fractions, the greatest quantitative increase was seen in phosphatidylcholine (more than twice thecontrol) and the smallest increase was seen in phosphatidylethanolamine (less than 1.6 times). After 6 and 12 mo, the values
were similar. Lung lipids had a greater range of values than did the phospholipids (no details given). The wet weight of thelung in grams increased in 5% to 10% Bentonite-treated rats compared to controls at month 3. No difference was detected

Distributed for Comment Only -- Do Not Cite or Quoteat 6 and 12 mo. Hydroxyproline content of treated rats (mg/g lung wet weight) was very similar to controls at 3, 6, and 12
mo.
Subplantar injections of 0.05 ml of a 5% solution of Bentonite were given to male Wistar rats.1 The rats either received
Bentonite injections in both hind paws at an interval of 24 h, or their left paw was injected with Bentonite and their right paw
injected with 0.05 ml of a 10% solution of Kaolin (control). Subcutaneous Bentonite granulomas were produced on the left
side, both dorsally and ventrally. Simultaneously, Kaolin granulomas were produced on the right side analogous to the
Bentonite injection. Sodium salicylate and prednisone suppressed the Bentonite edema during the first 24 h. The presence ofmononuclear cells was confirmed.
KaolinThe ability of Kaolin to increase susceptibility to bacterial pneumonia was studied in mice.1 The animals were injected
intratracheally with 100 µg Kaolin. In vivo bacterial infectivity screening assays were conducted by exposing the animals toaerosolized Group C Streptococcus species. The severity of infection was calculated by recording the deaths of the mice overa 15-day period. Control animals were exposed to titanium dioxide. A 100-µg dose of Kaolin caused statistically significant
but modest (<50%) increased death due to infection by a large dose. Mortality was calculated at 38.9%. Control dusts at
100 µg produced only a 5% increase in mortality.
DERMAL IRRITATION AND SENSITIZATION
Hectorite
A primary irritation study patterned after the Draize method was conducted using 6 white rabbits.1 Either a 0.5 ml or a
0.5 g sample of Hectorite was applied to two sites, one on abraded skin, and the other on intact skin of the backs of the
rabbits. The test sites were occluded for 24 h. At the end of the 24 h, the binders were removed and the sites were gently
wiped clean. One-half hour later, the sites were examined and scored for erythema and edema. The sites were examinedagain at 72 h. The average score was 0.0. Hectorite was nonirritating to the skin of rabbits.
In vitro, animal, and human dermal irritation, sensitization, and photoallergy studies are summarized in Table 6.
A formulation containing 38% Montmorillonite was predicted to be non-irritating in an EpiDerm™ skin model whentested neat.39 A clay product containing 75% illite, 19% Kaolin, and 6% Montmorillonite was not irritating to rabbit skinwhen tested at 500 mg in distilled water.28 A formulation containing 1.75% Bentonite was not irritating to human subjects in
a 14-d cumulative irritation assay, nor was a mud mask containing 8% Bentonite irritating in a single-insult occlusive patch
test40,41 No visible irritation was observed in a 4-wk clinical use test of a facial cleanser containing 2% Bentonite and 2%
Kaolin; however, some subjects reported perceived discomfort and/or irritation.42
A formulation containing 38% Montmorillonite was predicted to be non-sensitizing in a KeratinoSens™ assay.39 No
sensitization was observed in guinea pig studies of 50% Hectorite (Buehler test, details not provided) or of a clay productcontaining 75% illite, 19% Kaolin, and 6% Montmorillonite (intradermal induction at 5%; no further information on dosing
for topical induction or challenge provided).7,28 Dermal sensitization was not reported in human repeated insult patch tests(HRIPTs) with formulations containing Bentonite at up to 7.5%.43-45 No sensitization was observed in HRIPTs with a lip
product containing 14.5% Kaolin or a clay mask containing 40% Kaolin; however, one subject in a study of a clay mask
containing 14.5% Kaolin had moderate erythema progressing to erythema and edema with papules through the induction andchallenge phase.46-48 A sunscreen with 1.75% Bentonite was not a photosensitizer in humans.49
OCULAR IRRITATION STUDIES
AnimalHectorite
In a primary eye irritation study using 9 New Zealand white rabbits, a 0.1 ml liquid or semisolid (100 mg of the solid)
sample was instilled into the one eye of each rabbit.1 The eyes of 6 rabbits were not rinsed, and the eyes of 3 rabbits wererinsed approximately 4 s. All untreated eyes served as controls. The eyes were then examined with sodium fluorescein andan ultraviolet lamp at 24, 48, and 72 h and at 7 d. The mean score at 24 h was 2.0. All subsequent scores were 0.0. The test
sample was considered moderately irritating to rabbit eyes without rinsing and practically nonirritating to the eyes withrinsing 4 s after instillation.
KaolinThe potential for ocular irritation from a clay mask with 14.5% Kaolin was investigated in a tissue equivalent assay with
EpiOcular™ cultures.50 The EpiOcular™ human cell constructs were exposed to 100 µl test material under standard culture
conditions for 4, 8, 16, and 24 h. Tissue viabilities were then examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2Htetrazolium bromide (MTT) assay. The duration of exposure resulting in a 50% decrease of tissue viability (t50) was
calculated to be 5.2 h (at 4 h, tissue viability was 63.4%). The positive control yielded expected results. As residual test
article may bind to the tissue and result in a false MTT reduction signal, a freeze-killed tissue control was used, andDistributed for Comment Only -- Do Not Cite or Quotecalculations were performed to correct for the amount of MTT reduced directly by the test article residues in the tissues. The
clay mask with 14.5% Kaolin was predicted to not be an ocular irritant in this assay.
Kaolin and Montmorillonite
In an ocular irritation study performed in accordance with OECD TG 405, 100 mg of a clay product containing 75%
illite, 16% Kaolin, and 9% Montmorillonite was instilled into one eye of rabbits.28 The other eye served as a control and was
instilled with 0.1 ml normal saline. No adverse effects were noted following treatment up to 72 h after instillation. The test
material was considered to be non-irritating to rabbit eyes. No further details were provided.
CLINICAL STUDIESIn a study of total pulmonary non-asbestos mineral content in lung tissue from 20 individuals with no occupational dust
exposure, Attapulgite and Kaolin were identified in 12 individuals.1 No correlations were made between numbers or types offibers and age, sex, or smoking. Approximately 8400 out of 106,000 fibers (7.9%) were identified as Attapulgite andapproximately 3500 out of 106,000 fibers (3.3%) were identified as Kaolin. Mineralogical analysis found that 100% of the
Attapulgite fibers and 94% of the Kaolin fibers were 1 - 4.9 µm in length.
Oral
Montmorillonite
The effects of oral ingestion of Montmorillonite to protect against the adverse effects of the ingestion of aflatoxins werestudied in 23 male and 27 female human subjects.51 The subjects received 1.5 g/d or 3.0 g/d in capsules. A total of 9 capsules
were ingested over a 2-wk period. The study was randomized and double-blinded. Blood and urine samples were collected
before and after study. Mild gastrointestinal effects were reported with no statistical significance found between the groups
for these effects; no significant differences in hematology, liver and kidney function, or electrolytes were reported in eithergroup.
Bentonite

Case Reports

Several case studies involving Bentonite workers have been reported.1 Some milling plants had dangerous
concentrations of silica that ranged from 2 to 10 times the safe maximal concentration according to the US Bureau of Mines.
Silicotuberculosis developed in four patients studied.
Fuller’s EarthA patient that reported working no more than 15 yr in a Fuller’s Earth plant as a young man was diagnosed withterminal aspiration pneumonia, pneumoconiosis due to Fuller’s Earth exposure, bilateral emphysema, and fibrous pleuraladhesions.1 The lesions differed from typical silicotic lesions of the lungs; no formations of the whorled, acellular collagentypical of silicotic nodules were observed. Isolated cavities in the apices were filled with black sludge and surrounded by
vascular and cellular collagen. The dust in the lymph nodes had only stimulated the formation of reticulin fibers. No
subpleural nodules were present. At mineralogical analysis, the Fuller’s Earth deposits were constituted mainly ofMontmorillonite (85.2% to 90%).
Two additional cases of pneumoconiosis in employees that worked in processing or milling Fuller’s Earth for at least
28 yr were reported.1
KaolinA patient was reported with multiple pulmonary Kaolin granulomas.1 The man had a history of bilateral recurrent
pneumothorax. Both pleural spaces were destroyed with a suspension of liquid Kaolin. Recurrent right-sided pneumothorax
devolved and reobliteration was again performed. In a follow-up chest radiograph, multiple well-defined peripheral nodules
were in both lungs and pathological analysis revealed a bland acellular material surrounded by chronic inflammatory cells.
By light microscopy, the particles were consistent with Kaolin. It was presumed that Kaolin entered the lungs throughpleuroalveolar or pleurobronchial openings.
In another investigation, the death of a 62-yr-old man who worked in a cotton textile mill for 43 yr was reported.1 The
patient complained of progressive dyspnea and a productive cough. After being admitted to the hospital, a bronchoscopy
was performed and no endobronchial lesions were found. A lung biopsy had lesions of severe interstitial fibrosis withbronchioalveolar structures extensively involved in the fibrotic process. Pathological alterations such as bronchiolectasis,interstitial fibrosis with thickening of alveolar septa, mobilization of macrophages, and multinucleated giant cells wereidentified. Neither ferruginous bodies nor pleural hyaline plaque was identified. Kaolin particles were present with a mean
size of 0.88 µm. Chrysotile asbestos was also detected, but the majority of particles were Kaolin. The man died as aconsequence of respiratory failure despite an aggressive therapy of antibiotics and tuberculosis therapy.
The lungs and chest x-ray films were evaluated in a pair of case studies of men who worked in a Kaolin-processing
plant for many years.1 The first case was a 36-yr-old man who worked on the plant for 17 yr. Chest films were taken at theDistributed for Comment Only -- Do Not Cite or Quoteend of his career and detected lesions of extensive confluent consolidation and nodule formation of advanced
pneumoconiosis with infection. Autopsy and microscopic findings included alveolar spaces uniformly expanded, three areasof whorled fibrous tissue, scattered areas of cystic spaces, hilar nodes heavily pigmented, deposits of brownish black
particulate matter, a large vessel with recent thrombus, hemorrhage, and necrosis, marked fibrous thickening of the pleura,and dense fibrous scarring of the lymph nodes. The final diagnosis was pneumoconiosis (kaolinosis) with pulmonary
thrombosis and infarction of the lungs. The second case study was a 35-yr-old man who worked in the Kaolin-processing
plant for 21 yr. Within his last 3 yr, he had dyspnea and a slight cough with small amounts of dark colored sputum. The
sputum was negative for bacteria. Chest films revealed advanced pneumoconiosis with infection, confluent consolidation,
nodular infiltration, cavitation, and emphysema. Autopsy and microscopic findings included nodules in the right and middle
lobes, pleural spaces were thickened and shaggy, large bulbous emphysematous blebs, a pulmonary artery with organizing
thrombus, heavily pigmented hilar lymph nodes, whorled fibrous collagenous tissue, and spaces and walls withmacrophages. The final diagnosis was pneumoconiosis (kaolinosis).
A 35-yr-old man who worked at a Kaolin-processing plant for 17 yr presented with chest pain and was hospitalized.1
For the previous 2 yr before admittance, the man had packaged dried, processed Kaolin. Chest films revealed diffuse
reticulonodular pulmonary infiltrates and a well-defined, noncalcified mass in the upper right lobe. A thoracotomy was
performed and an 8 cm x 12 cm x 10 cm conglomerate pneumoconiotic lesion containing large amounts of Kaolin was found.
X-ray diffraction material from the lesion had peaks corresponding to Kaolinite. The presence of silica was not confirmed by
x-ray diffraction.
Pulmonary tissue was obtained from 5 Kaolin workers with advanced pneumoconiosis.1 Chest radiographs detected
small irregular shadows and large opacities typical of Kaolin pneumoconiosis. At autopsy, firm, grey-brown nodules andmasses were in the parenchyma and in the hilar lymph nodes. Microscopic lesions were extensive pulmonary Kaolinite
deposition associated with the formation of peribronchiolar nodules. The nodules were comprised of Kaolinite aggregatestransversed by bands of fibrous tissue rather than dense whorled collagen. Kaolin was detected in the lungs. Silica was notdetected by either analytical scanning electron microscopy or x-ray diffractometry.
Six additional cases of pneumoconiosis in employees of 12 yr in Kaolin processing or milling facilities were reported.1
Montmorillonite
A 73-yr-old Montmorillonite worker developed signs of pneumoconiosis, but subsequently died of acute gastrointestinal
hemorrhage from a benign gastric ulcer.1 A chest radiograph taken 2 yr before his death showed a bilateral finereticulonodular shadowing, while another radiograph taken a few weeks before his death indicated a slight increase in thereticulonodular opacities and a mass at the left hilum and apex. At autopsy, numerous soft stellate grey-black dust lesions 4- 5 mm in diameter were observed occupying most of the lungs. No lesions of progressive massive fibrosis were identified.
Also present were lesions of severe emphysema and a 4 cm diameter neoplasm arising from the bronchus of the left upper
lobe. At microscopic examination, numerous interstitial collections of dust-laden macrophages were situated around therespiratory bronchioles and along the adjacent alveolar septa. A slight degree of fibrosis associated with the dust lesions
was observed, and the neoplasm was a poorly differentiated adenocarcinoma containing giant cell areas. Mineralogicalanalysis showed a large amount of calcium Montmorillonite.
OCCUPATIONAL EXPOSURE
Attapulgite
A cohort of 2302 men employed for at least 1 mo between January 1, 1940 and December 31, 1975 at an Attapulgite
mining and milling facility was studied.1 A significant deficit of mortality from nonmalignant respiratory disease wasobserved based on age, calendar year, and rates. A marked deficit of nonmalignant respiratory disease was seen regardlessof presumed dust exposure level, induction-latency period, or duration of employment. A statistically significant excess ofmortality from lung cancer was observed among whites, but a deficit occurred among nonwhites. Lung-cancer risk in either
race was not altered substantially with presumed dust exposure level, induction-latency period, or duration employed, with
one exception—those employed for at least 5 yr in high-exposure level jobs. An increased mortality was observed for gastriccancer (6 observed) and a deficit due to nonmalignant respiratory disease was observed (9 observed).
KaolinA study was performed on the prevalence of ventilatory impairment, chest symptoms, and radiographic abnormalities inover 2000 Kaolin workers representing over 95% of the current employees in the industry.1 Of the participants, 19%
admitted having a cough. Of those participants with a cough, 17% had an abnormal forced expiratory volume and 14% had
an abnormal vital capacity. Of those without a cough, 5.5% had an abnormal forced expiratory volume and 7% had anabnormal vital capacity. Also, 18% of the participants admitted to chronic sputum production. Of those with sputum
production, 16% had abnormal forced expiratory volume, and 12.5% had abnormal vital capacity. Of those without the
production, 6% had an abnormal forced expiratory volume, and 7.5% had an abnormal vital capacity. About 30% of theparticipants complained of shortness of breath, 3.1% was classified as severe. Wheezing was reported by 29% of thesubjects. Satisfactory chest films for 2069 of the subjects were available for examination. Radiographic findings of 90

Distributed for Comment Only -- Do Not Cite or Quote

subjects revealed simple pneumoconiosis. Eighteen subjects (0.89%) had complicated pneumoconiosis. Of men with eithercase of pneumoconiosis, 51.1% were dry processors, compared to 6.3% of the men who worked in wet processing. Of thenonsmoking participants (549), 542 and 537 men had a satisfactory forced expiratory volume and forced vital capacity,respectively, in addition to an acceptable chest radiograph. Of these nonsmoking workers, 516 were studied for dust
exposure and pulmonary function. Among the nonsmokers with no pneumoconiosis, those persons working in calcined clay
had a greater prevalence of lung function abnormalities. This group had a significant increase in the risk of having anabnormal forced expiratory volume but tended to have less incidences of pneumoconiosis. In short, ventilatory impairment
was related to the presence of complicated pneumoconiosis, employment in clay calcining, and cigarette smoking. Also workin dry processing was associated with a greater risk of developing pneumoconiosis.
The lungs of 62 recently deceased men between the years of 1968 to 1981 were taken for an assessment of the severityof lung disease.1 Fifty-four of the 62 men worked with Kaolin or related kaolinized mineral stone. All the test subjects were
employed in the mining industry. Chest radiographs were available for 39 of the 62 cases. Sections of lung tissue were
examined microscopically for nodular and interstitial fibrosis and an overall grade ranging from 0 (none) to 3 (severe).
Samples from 42 cases were analyzed for mineral content by x-ray diffraction and lung-dust concentrations. Radiographic
lesions included 13 cases of progressive massive fibrosis and 22 cases of simple pneumoconiosis. Only four cases had noevidence of any disease. Nodular opacities tended to reflect a high quartz content, whereas high-Kaolin lung content had
interstitial changes and irregular radiological changes. An increasing quartz concentration appears to be related to nodular
fibrosis. The degree of interstitial fibrosis appeared to be more related to dust lung concentrations, although these results
failed to reach statistical significance.
The Occupational Safety and Health Administration (OSHA) lists the following permissible exposure limit (PEL) for
8-h work shifts for Kaolin: total dust - 15 mg/m3 and respirable fraction - 5 mg/m3.52 The National Institute for Occupational
Safety and Health (NIOSH) lists the following recommended exposure limit (REL) for up to 10-h time weighted average for
Kaolin: total dust - 10 mg/m3 and respirable fraction - 5 mg/m3.
Bentonite
In a toxicological and occupational epidemiological review of Bentonite, the authors concluded Bentonite is probably
not more toxic than any other inert insoluble dusts.53 However, because some forms may contain variable amounts of
respirable crystalline silica, prudent management and adherence to occupational exposure limits is appropriate.
SUMMARY
This report assesses the safety of 7 clay ingredients as used in cosmetics. All of these ingredients are reported tofunction as absorbents and bulking agents; other cosmetic functions are also reported. The Panel previously reviewed thesafety of Attapulgite, Bentonite, Fuller’s Earth, Hectorite, Kaolin, and Montmorillonite in a report that was published in
2003. In that report, the Panel concluded that these ingredients were safe as used in cosmetic ingredients. In accordance with
its Procedures, the Panel evaluates the conclusions of previously-issued reports approximately every 15 yr, and it has been atleast 15 yr since this assessment has been issued.
According to 2022 VCRP survey data, Kaolin has the most reported uses in cosmetic products, with a total of 1046; themajority of uses are in leave-on formulations. Bentonite has the second most reported uses in cosmetic products, with a totalof 262; a little more than half are reported in leave-on formulations. The frequencies of use for both of these ingredients havegreatly changed since the original safety assessment was finalized; in 1998, Kaolin was reported to have 509 uses andBentonite was reported to have 94. The results of concentration of use surveys conducted by the Council in 2022 indicate
Kaolin also has the highest concentration of use in a leave-on formulation; it is used at up to 53.2% in manicuring
preparations. Bentonite is reported to have a maximum concentration of use for leave-on products of 8% in skin care
preparations. According to the original safety assessment, the maximum leave-on use concentration in 1999 for Kaolin was
100% in skin care preparations; the maximum leave-on use concentration for Bentonite was 8% in makeup foundations.
drug.

Several of these clay ingredients are GRAS as direct and/or indirect food additives. Kaolin is also an approved OTC

Ex vitro bioavailability studies were performed using human skin models. Trace heavy metals in 3 clay pastes (whiteMontmorillonite, Kaolin, and a clay product containing 75% illite, 19% Kaolin, and 6% Montmorillonite) did not penetratecutaneous tissue.
In acute dermal and oral toxicity studies in rats, a clay product containing 75% illite, 19% Kaolin, and 6%
Montmorillonite had an LD50 greater than 2000 mg/kg. The same product was tested in an acute inhalation study in rats andhad an LC50 greater than 3.856 mg/l.
In a 90-d oral study in male rats, a modified Montmorillonite clay at 40 mg/kg/d did not cause any deaths during
treatment, and no significant changes were noted in clinical biochemistry, organ weights, or in histopathologicalexaminations when compared to controls. A naturally-occurring calcium Montmorillonite clay produced non-dosedependent significant changes in mean corpuscular hemoglobin, serum calcium, serum vitamin A, and serum iron when

Distributed for Comment Only -- Do Not Cite or Quote

tested at up to 2.0% w/w in rats in a dietary study; however, no adverse effects were noted in feed consumption, body weight,organ weights, or in gross or histopathological exams.
A clay product containing 75% illite, 19% Kaolin, and 6% Montmorillonite (5000 µg) was not mutagenic in an Ames
test, with or without metabolic activation. Unmodified Montmorillonite clay (at up to 125 µg/ml) and one type of cationexchanged Montmorillonite clay (at up to 250 µg/ml) also were not mutagenic in an Ames test with or without metabolic
activation, but significant increases in revertant colonies were observed in one strain with metabolic activation in 2 othercation-exchanged Montmorillonite clays. No mutagenic activity was observed in a Salmonella/microsome assay with andwithout metabolic activation when tested in Montmorillonite and cation-exchanged montmorillonite in both nano- and nonnano-sized material at up to 141 µg/ml and up to 14.1 µg/plate, respectively. However, the cation-exchanged
Montmorillonite material (both nano- and non-nano-sized, at up to 226 µg/ml and 170 µg/ml, respectively) in this study was
genotoxic in a concentration-related manner in a Comet assay with Caco-2 cells. A clay product containing 75% illite, 19%
Kaolin, and 6% Montmorillonite did not induce chromosomal aberrations in CHO cell cultures when tested at up to 5000
µg/ml, with or without metabolic activation. Statistically significant increases in the frequency of micronuclei were induced
by Montmorillonite clay at 62.5 µg/ml in a cytokinesis block micronucleus cytome assay in human hepatoma cell lines, but
this effect was not observed at a concentration of 31.25 µg/ml or lower. No effects in nucleoplastic bridges or nuclear buds
were observed at any concentration in this study. In an in vitro micronucleus assay and kinetochore analysis using humanlung fibroblasts, the genotoxic potential of Bentonite at up to 15 µg/cm2 was determined to be generally low, but could bealtered by the content of quartz and available transition metals. In an in vivo Comet assay in rats with cation-exchanged
montmorillonite clay at up to 1000 mg/kg bw given orally, no statistically significant difference in % tail DNA between thenegative controls and the different treatment groups for any of the cells (liver, kidneys, colon) tested.
IARC has determined there is inadequate evidence in humans for the carcinogenicity of Attapulgite. Further, IARC hasdetermined there is insufficient evidence in experimental animals for the carcinogenicity of short Attapulgite fibers (< 5 µm);
however, there is sufficient evidence in experimental animals for the carcinogenicity of long Attapulgite fibers (> 5 µm).
Overall, long Attapulgite fibers (> 5 µm) are possibly carcinogenic to humans (Group 2B) and short Attapulgite fibers (< 5µm) cannot be classified as to its carcinogenicity to humans (Group 3). Attapulgite (palygorskite fibers > 5 µm in length) islisted by California Proposition 65 as a carcinogen.
The ability for Bentonite (2/3 weight) and a zeolite (type not specified; 1/3 weight) to act as a hemostatic agent wasstudied in 12 male Sprague-Dawley rats. This hemostatic agent may cause vasoconstriction and inhibition of
neoangiogenesis.
A formulation containing 38% Montmorillonite was predicted to be non-irritating in an Epiderm™ skin model whentested neat. A clay product containing 75% illite, 19% Kaolin, and 6% Montmorillonite was not irritating to rabbit skin whentested at 500 mg in distilled water. A formulation containing 1.75% Bentonite was not irritating to human subjects in a 14-dcumulative irritation assay, nor was a mud mask containing 8% Bentonite irritating in a single-insult patch test. No visible
irritation was observed in a 4-wk clinical use test of a facial cleanser containing 2% Bentonite and 2% Kaolin; however,some subjects reported perceived discomfort and/ or irritation.
A formulation containing 38% Montmorillonite was predicted to be non-sensitizing in a KeratinoSens™ assay. No
sensitization was observed in guinea pig studies of 50% Hectorite (further dosing information not provided) or a clay productcontaining 75% illite, 19% Kaolin, and 6% Montmorillonite (intradermal induction at 5%, no further information on dosing
for topical induction or challenge provided). Dermal sensitization was not reported in HRIPTs with formulations containing
Bentonite at up to 7.5%. No sensitization was observed in HRIPTs with a lip product containing 14.5% Kaolin or a clay
mask containing 40% Kaolin; however, one subject in a study of a clay mask containing 14.5% Kaolin had moderate
erythema progressing to erythema and edema with papules through the induction and challenge phase. A sunscreen with
1.75% Bentonite was not a photosensitizer in humans.
A clay mask with 14.5% Kaolin was predicted to not be an ocular irritant in a tissue equivalent assay with EpiOcular™ .
In an ocular irritation study in rabbits, a clay product containing 75% illite, 19% Kaolin, and 6% Montmorillonite produced
no adverse effects and was considered to be non-irritating.
Nine capsules containing Montmorillonite (up to 3.0 g/d) was administered to 50 human subjects over a 2-wk period.
Only mild gastrointestinal effects were reported.
OSHA lists the following PEL for 8-h work shifts for Kaolin: total dust - 15 mg/m3 and respirable fraction - 5 mg/m3.
NIOSH lists the following REL for up to 10-h time weighted average for Kaolin: total dust - 10 mg/m3 and respirable fraction- 5 mg/m3. In a toxicological and epidemiological review of Bentonite, the authors concluded Bentonite is probably not more
toxic than any other particulate. However, because some forms may contain variable amounts of respirable crystalline Silica,
prudent management and adherence to occupational exposure limits is appropriate.
PREVIOUS DISCUSSION
The Panel determined that the data provided in this report are sufficient to assess the safety of … Attapulgite, Bentonite,
Fuller’s Earth, Hectorite, Kaolin…Montmorillonite…1 The Panel did note a concern about inhalation of these ingredientsDistributed for Comment Only -- Do Not Cite or Quote

due to reported cases of pneumoconiosis and fibrosis in humans and pulmonary lesions in animals. However, extensive
pulmonary damage in humans was the result of direct occupational inhalation of the dusts and lesions seen in animals wereaffected by particle size, fiber length, and concentration. The Panel recognizes that most of the formulations are notrespirable and of the preparations that are respirable, the concentration of the ingredient is very low. Even so, the Panelconsidered that any spray containing these solids should be formulated to minimize their inhalation.
DRAFT DISCUSSION
In accordance with its Procedures, the Panel evaluates the conclusions of previously-issued reports approximately every
15 years. In 2003, the Panel published a final report on Attapulgite, Bentonite, Fuller’s Earth, Hectorite, Kaolin, andMontmorillonite, and concluded that the ingredients named in that report were safe as used in cosmetic products. This reporthas been reopened to include additional ingredients. Thus, this current assessment reviews the safety of 8 naturally-sourced
clay ingredients as used in cosmetic formulations. In this amended report, the Panel concluded that the available data are…(to be determined).
Although heavy metal contaminates (e.g., lead, mercury, nickel) may be present during mining, those should be readily
separable. Accordingly, the Panel stressed that the cosmetics industry should continue to use current good manufacturing
practices (cGMPs) to limit these heavy metal contaminates before blending into cosmetic formulations.
Additionally, some naturally-sourced clay ingredients were reported to be used in spray and powder products that could
possibly be inhaled. For example, Bentonite is reported to be used at 0.9% in spray suntan product and Kaolin is reported to
be use at up to 15% in face powders. The Panel noted that Attapulgite with long fibers (> 5 µm) is possibly carcinogenic tohumans and animals. Additionally, the Panel noted that Bentonite may contain as an impurity crystalline silica (cristobalite),
which is also a human carcinogen. Because the potential of adverse health effects from inhalation of carcinogenic materials,
the Panel determined that Attapulgite and Bentonite should not be used in cosmetic formulations which may be incidentally
inhaled.
With the exception for Attapulgite and Bentonite, the limited data available from inhalation studies, including acute,chronic, and carcinogenicity data, suggest little potential for respiratory effects at relevant doses for the remaining naturallysourced clay ingredients. The Panel noted that in aerosol products, the majority of droplets/particles would not be respirable
to any appreciable amount. Furthermore, droplets/particles deposited in the nasopharyngeal or tracheobronchial regions of
the respiratory tract present no toxicological concerns based on the chemical and biological properties of these ingredients.
Coupled with the small actual exposure in the breathing zone and the low concentrations at which the ingredients are used (orexpected to be used) in potentially inhaled products, the available information indicates that incidental inhalation would not
be a significant route of exposure that might lead to local respiratory or systemic effects. A detailed discussion and summaryof the Panel’s approach to evaluating incidental inhalation exposures to ingredients were also included in the Panel’s
respiratory exposure resource document (https://www.cir-safety.org/cir-findings).
The Panel’s respiratory exposure resource document (see link above) notes that airbrush technology presents a potential
safety concern, and that no data are available for consumer habits and practices thereof. As a result of deficiencies in these
critical data needs, the safety of cosmetic ingredients applied by airbrush delivery systems cannot be determined by the Panel.
Therefore, the Panel has concluded the data are insufficient to support the safe use of cosmetic ingredients applied via an
airbrush delivery system.
CONCLUSION
To be determined…

Distributed for Comment Only -- Do Not Cite or Quote

TABLES
Table 1. Definitions and reported cosmetic functions of the ingredients in this safety assessment.2
Ingredient, CAS No.
Definition
Attapulgite
Attapulgite is a variety of Fuller's Earth found typically near Attapulgas,
12174-11-7
Georgia. It is characterized by having a chain structure rather than the1337-76-4
usual sheet structure of other clay minerals.
Bentonite
Bentonite is a native hydrated colloidal aluminum silicate clay.
1302-78-9
Clay53801-44-8
Fuller’s Earth8031-18-3
Hectorite
12173-47-6
68084-71-9

Clay is a group of phyllosilicate minerals produced by the chemical andphysical weathering of rock. It consists chiefly of varying amounts ofhydrated silica and alumina, and is characterized by a particle size of lessthan 2 micrometers.
Fuller's Earth is a non-plastic variety of kaolin containing an aluminummagnesium silicate.
Hectorite is one of the montmorillonite minerals that are the principal
constituents of bentonite clay.

Kaolin1332-58-7

Kaolin is a native hydrated aluminum silicate with an approximate
composition of Al2O3 ∙ 2SiO2 ∙ 2H2O.

Montmorillonite
1318-93-0

Montmorillonite is a complex aluminum/magnesium silicate clay.

Reported Functions
Abrasives; Absorbents; Bulking Agents;
Opacifying Agents; Viscosity Increasing
Agents - Aqueous
Absorbents; Bulking Agents; Dispersing
Agents - Nonsurfactant; Emulsion
Stabilizers; Opacifying Agents; Viscosity
Increasing Agents - Aqueous
Absorbents; Binders; Bulking Agents;
Skin-Conditioning Agents - Misc.;
Viscosity Increasing Agents - Aqueous
Abrasives; Absorbents; Anticaking Agents;
Bulking Agents; Opacifying Agents
Absorbents; Bulking Agents; Dispersing
Agents - Nonsurfactant; Opacifying
Agents; Viscosity Increasing Agents Aqueous
Abrasives; Absorbents; Anticaking Agents;
Bulking Agents; Opacifying Agents; Skin
Protectants; Slip Modifiers
Abrasives; Absorbents; Bulking Agents;
Emulsion Stabilizers; Opacifying Agents;
Viscosity Increasing Agents - AqueousDistributed for Comment Only -- Do Not Cite or Quote
Table 2. Physical and chemical properties
Property
Value

Reference
Attapulgite

Physical FormWhite, gray, or transparent, dull, elongated, lath-shaped crystals in bundles that comprise thin sheetsof minute interlaced fibers; surface is protonated and hydrated

1

Chemical Formula

Mg(Al0.5-1Fe0-0.5)Si4O10(OH)·4H2O

1

Density (g/ml)

2.2

1

Solubility

Insoluble in water

1

Particle Size/Length (µm)<51Physical Form

Crystalline, claylike material, available as an odorless, pale buff or cream to grayish-colored fine
powder, which is free from grit; dioctahedral

1

Chemical Formula

Al2O3·4SiO·2H2O

1Formula Weight (Da)359.16

1

Solubility

Insoluble in water, alcohol, fixed oils, glycerin, dilute acid, and alkali solutions

1,5

Particle Size/Length (µm)

Mainly 50-150 with some 1-2

1

Physical Form

Non-plastic variety of Kaolin; sheet structure

Physical Form

Translucent colorless mineral when mined and turns white when dried; tridecahedral

1

Chemical FormulaNa0.33(Mg2.67Li0.33)Si4O10(OH)2

1

Specific Gravity (g/ml)

2.65

1

Physical FormWhite or yellowish white, earthy mass or white powder; unctuous when moist

1

Chemical Formula

Al2O3·2SiO2·2H2O

1Formula Weight (Da)

258.2

1

Solubility

Insoluble in water, alcohol, dilute acids, and alkali solutions

1,5

Chemical FormulaR+0.33(Al, Mg)2Si4O10(OH)2, where R+ = Na+, K+, Mg2+ or Ca2+

Bentonite

Fuller’s Earth1

Hectorite

KaolinMontmorillonite

Table 3. Raw material specifications for a product containing 75% illite, 19% Kaolin, and 6% Montmorillonite8
AspectBeige green powder
Odor
None
pH
Between 8 and 9
Grain size
Variation 1: 80% < 5 µm; 100% < 10 µm
Variation 2: 90% < 20 µm; 100% < 40 µm
Variation 3: 90% < 77 µm; 100% < 100 µm
Variation 4: 90% < 750 µm; 100% < 1100 µm

1Distributed for Comment Only -- Do Not Cite or Quote
Table 4. Frequency and concentration according to duration and type of exposure for clay ingredients.1,16,17
Attapulgite# of Uses
Max Conc of Use (%)
2022
1998
2022
1999
Totals*
3
10
NR
8

2022
262

Leave-On
Rinse-Off
Diluted for (Bath) Use

NR
3
NR

5
5
NR

NR
NR
NR

8
8
NR

Eye Area
Incidental Ingestion
Incidental Inhalation-Spray
Incidental Inhalation-Powder
Dermal Contact
Deodorant (underarm)
Hair - Non-Coloring
Hair-Coloring
Nail
Mucous Membrane
Baby Products

NR
NR
NR
NR
3
NR
NR
NR
NR
NR
NR

NR
NR
NR
5
10
NR
NR
NR
NR
NR
NR

NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR

NR
NR
8b
8b
8
NR
NR
NR
NR
NR
NR

# of Uses

Clay

Bentonite
1998
94

Max Conc of Use (%)
2022
1999
0.00025-17.3
0.5-80

131
118
13

37
57
NR

0.00025-8
0.22-17.3
NR

0.8-8
0.5-80519823a; 42b1; 42b
212
NR
8
NR
24
30
2

8
NR
5 a; 7 b
7b
88
NR
4
NR
1
3
NR

0.00025-4.5
NR
0.9
8c
0.00025-10
NR
NR
17.3
2.8
0.22-4.7
NR

0.8-5
NR
1-3a; 2-5b
2-5b
0.5-80
NR
NR
NR
1
0.5-5
NR

NA
NA

Max Conc of Use (%)
2022
NA
4.5
NA

2022
9

# of Uses# of Uses

Fuller’s Earth
Max Conc of Use (%)
1998
2022
1999
3
NR
NR

Totals*2022
59

Leave-On
Rinse-Off
Diluted for (Bath) Use

40
17
2

NA
NA
NA

NR
4.5
NR

NA
NA
NA

2
7
NR

1
2
NR

NR
NR
NR

NR
NR
NR

12
10
1a; 11b
1; 11b
42
2a
4
NR
NR
16
NR

NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA

NR
NR
NR
NR
4.5
NR
NR
NR
NR
NR
NR

NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA

NR
NR
1a
NR
8
NR
1
NR
NR
1
NR

NR
NR
NR
NR
3
NR
NR
NR
NR
NR
NR

NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR

NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR

Eye Area
Incidental Ingestion
Incidental Inhalation-Spray
Incidental Inhalation-Powder
Dermal Contact
Deodorant (underarm)
Hair - Non-Coloring
Hair-Coloring
Nail
Mucous Membrane
Baby Products# of Uses

Hectorite
1998
18

Max Conc of Use (%)
2022
1999
0.057-1.5
0.4-100

2022
59# of Uses

IlliteNA
NA

Max Conc of Use (%)
2022
NA0.0015-3.8
NATotals*2022
50

Leave-On
Rinse-Off
Diluted for (Bath) Use

34
16
NR

10
8
NR

0.057-1.5
0.1-0.13
NR

0.7-15
0.4-100
NR

31
26
2

NA
NA
NA

0.0015-0.025
0.34-3.8
NR

NA
NA
NA

17
NR
3 a; 5 b
1; 5b; 1c
35
NR
5
1
1
NR
1

4
NR
1a
NR
10
1a
NR
5
2
1
NR

0.057
NR
NR
0.1c
0.057-1.5
NR
0.1-0.13
0.1
NR
NR
NR

0.7
NR
8b
8b
0.4-100
0.7a
1
NR
NR
NR
NR

NR
1
4a; 18b2; 18b
55
NR
3
NR
NR
4
NR

NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA

NR
NR
0.25a
NR
0.0015-3.8
NR
0.25
NR
NR
0.34
0.0015

NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA

Eye Area
Incidental Ingestion
Incidental Inhalation-Spray
Incidental Inhalation-Powder
Dermal Contact
Deodorant (underarm)
Hair - Non-Coloring
Hair-Coloring
Nail
Mucous Membrane
Baby Products

Distributed for Comment Only -- Do Not Cite or Quote
Table 4. Frequency and concentration according to duration and type of exposure for clay ingredients.1,16,17
Kaolin# of Uses
Max Conc of Use (%)
2022*
1998
2022
1999
Totals*1046
509
0.0005-53.2
0.01-100

2022
75

Leave-On
Rinse-Off
Diluted for (Bath) Use

26
47
2

707
320
19

501
7
1

0.0015-53.2
0.0005-33
NR

2-100
0.01-84
NR# of Uses

Montmorillonite
Max Conc of Use (%)
1998
2022
1999
NR
0.1-3
NR
NR
NR
NR

1.2-2
0.1-3
NR

NR
NR
NR

Eye Area201
231
0.001-8.5
3-48
2
NR
NR
Incidental Ingestion
150
60.0053-14.5
12-30
1
NR
NR
Incidental Inhalation-Spray
1; 50a; 87b
NR0.0015-25a
2-25a; 3b7a; 11b
NR
NR
Incidental Inhalation-Powder
53; 87b; 1c
98
0.01-15; 0.11-16c
5-30; 3b11bNR
1.2-2cDermal Contact
798
466
0.001-33
0.01-100
68
NR
0.1-3
Deodorant (underarm)
7a
NR
2.6
NR
NR
NR
NR
Hair - Non-Coloring
47
50.0005-26
4-15
6
NR
NR
Hair-Coloring
13
1
5-19.5
NR
NR
NR
NR
Nail
9
NR
0.023-53.2
53-54
NR
NR
NR
Mucous Membrane
193
80.0053-14.5
3-30
12
NR
NR
Baby Products
1NR
0.0085NR
NR
NR
NR
NR = Not reported. NA = Not applicable.
* Includes entries for Kaolinite from the VCRP database.
† Because each ingredient may be used in cosmetics with multiple exposure types, the sum of all exposure types may not equal the sum of total uses.
a.
It is possible these products may be sprays, but it is not specified whether the reported uses are sprays.
b.
Not specified whether a powder or a spray, so this information is captured for both categories of incidental inhalation.
c.
It is possible these products may be powders, but it is not specified whether the reported uses are powders.

NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR

Distributed for Comment Only -- Do Not Cite or Quote
Table 5. Genotoxicity studies
Test Article

Concentration/Dose

VehicleTest System

Procedure

Results

Reference

S. typhimurium strains
TA98, TA100, TA102,
TA1535, TA1537
S. typhimurium strains
TA97A, TA98, TA100,
TA102, TA104

Ames test in accordance with OECD TG 471;with and without metabolic activation

Not mutagenic with or without metabolic
activation

28

Ames test; with and without metabolic
activation

31

0-14.1 µg/plate for unfiltered MilliQ water
material; 0-141 µg/ml for
filtered material (particles
larger than nano-range
removed)56.5, 85, 113, or 170 µg/ml
culture medium
for unfiltered material; up to
226 µg/ml for filteredmaterial (particles larger thannano-range removed)

S. typhimurium TA98 andTA100

Salmonella/microsome assay; with andwithout metabolic activation; suspensions
were tested both filtered (removing particle
larger than nano-range) and unfiltered material

No significant increases in revertant colonies
observed in the unmodified clay (tested at up
to 125 µg/ml) or in one of the modified clays(tested at up to 250 µg/ml); however,significant increases in revertant colonies
observed in S9 in strain TA98 in the othertwo modified clays (tested at up to 8 µg/ml
and 125 µg/ml, respectively); no changes
observed for the same strain without S9 or in
the rest of the strains for these 2 modified
clays
No mutagenic activity observed with orwithout metabolic activation

Caco-2 cells

Comet assay; suspensions were tested both
filtered (removing particle larger than nanorange) and unfiltered material

32

156.25, 312.5, 625, 1250,
2500, or 5000 µg/ml

culture medium

CHO - K1 cell cultures

15.65, 31.25, or 62.5 µg/ml

serum-free medium Human hepatoma cell lines
supplemented with (HepG2)
B27 (no further
details on
supplement)

Unfiltered and filtered modified
Montmorillonite was genotoxic in aconcentration-related manner, with statisticalsignificance at the 2 highest concentrations
tested for each, when compared to negative
controls; no genotoxic effects were observedin the unfiltered and unfiltered natural
Montmorillonite
Mammalian chromosome aberration test in
Test material did not induce chromosomal
accordance with OECD TG 473; with andaberrations, with or without metabolic
without metabolic activation
activation
Cytokinesis block micronucleus cytome assay; Test material induced statistically significant
cells were incubated with test material for 4 or increases (p < 0.0001) only in the frequency
24 h; positive controls were benzo(α)pyreneof micronuclei in 1000 binucleated cells atand etoposidethe highest concentration tested; no effects
observed in nucleoplasmic bridges or
nuclear buds; positive controls yielded
expected results

IN VITRO
Clay product containing
75% illite, 16% Kaolin,
and 9% Montmorillonite
Montmorillonite-based
clay minerals (1unmodified clay and 3
cation-exchanged clays

Montmorillonite, naturaland oragno-modified

Montmorillonite, naturaland cation-exchanged

Clay product containing
75% illite, 16% Kaolin,
and 9% Montmorillonite
Unmodified
Montmorillonite clay

5000 µg

Not reported

unmodified clay tested at up
to 125 µg/ml; modified clays
tested at up to 250 µg/ml

MilliQ water

32

28

33

Distributed for Comment Only -- Do Not Cite or Quote
Table 5. Genotoxicity studies
Test Article

Concentration/Dose

Bentonite particles with α- 1 to 15 µg/cm2
quartz content (up to 6%)
and with different chemical
modifications (acid,alkaline, organic,
untreated); gypsum andquartz were negative andpositive controls

Vehicleisotonic NaClsolution

Test System

Procedure

Results

Human lung fibroblasts(IMR90)Micronucleus assay and kinetochore analysis;treated cells incubated for 36, 48, or 72 h

In acidic sample, formation of micronuclei
was only slightly increased after exposure to
samples with a quartz content of 4% - 5%
for 36 h (15 µg/cm2), 48 h (5 µg/cm2), and
72 h (1 µg/cm2); and with a quartz content of
1% for 72 h (1 µg/cm2).

Reference34

In the alkaline sample, the formation of
micronuclei was only slightly increased after
exposure to sample with a quartz content of
5% for 48 h and 72 h (15 µg/cm2).
Untreated and organic activated Bentonite
particles did not show genotoxic effects;
Bentonite particles with a quartz content of< 1% were in negative in the micronucleus
assay.
Statistically significant reductions in
kinetochore-positive micronuclei were notobserved with the Bentonite samples
IN VIVO

cation-exchanged
Montmorillonite

0, 250, 500, or 1000 mg/kg
bw; 1000 mg/kg bw in range
finding study

Water or cellculture medium

Groups of 3 male and 3
female Wistar Hannover
Galas rats; 2 rats of eachsex in a range finding study

Comet assay; rats received 2 single doses of
No statistically significant difference in %test material by gavage 24 h apart; 3 h after
tail DNA between the negative controls anddosing, rats were killed and examinedthe different treatment groups for any of themacroscopically, and liver, kidneys, and colon organs tested for DNA damage; positive
were dissected and analyzed for DNA damage; control yielded expected results; all rats
survived during treatment period with nowater or cell-culture medium was negative
clinical signs of abnormalities
control and ethylmethanesulfonate waspositive control

35

Distributed for Comment Only -- Do Not Cite or Quote
Table 6. Dermal irritation and sensitization studies
Test Article

Formulation containing 38%
Montmorillonite

VehicleConcentration/Dose

25 µl calcium andTested neat; 25 mg
magnesium freeDulbecco’s phosphatebuffered saline

Clay product containing 75% illite, 0.5 ml distilled water
16% Kaolin, and 9%
Montmorillonite

Formulation containing 1.75%
Bentonitenone

Mud mask containing 8%
Bentonite
Facial cleanser containing 2%
Bentonite and 2% Kaolin

none

Formulation containing 38%
Montmorillonite

Cell culture medium

50% Hectorite

Not reported

none

Clay product containing 75% illite, Distilled water
16% Kaolin, and 9%
Montmorillonite

Test Population

Procedure

Results

IRRITATION
IN VITRO
EpiDerm™ tissues EpiDerm™ skin model in accordance with OECD TG 439 Not an irritant; mean viability =105.7%ANIMAL
Acute dermal irritation study in accordance with OECD
Not irritating; mean dermal irritation
TG 404; patches were applied to intact skin with gauze
scores for erythema and edema werepatch for 4 h; after exposure period, residual test substance 0.0
was removed with cotton soaked in distilled water; skinreactions scored at 1, 24, 48, and 72 h post-patch removal
HUMAN
0.05 ml
25 subjects
14-d cumulative irritation assay under occlusive patches; Irritation potential was negligible; notest sites on the back or upper arm and patches were 15
adverse events reported
mm diameter disks; positive control site received 0.05 mlof 0.25% sodium lauryl sulfate and negative control site
was a plain patch
As supplied
19 subjects
Single-insult occlusive patch test
No irritation; primary irritation index =0.0
As supplied
50 subjects
4-wk clinical use test; single-blind baseline controlled
No visible irritation; however, 8monadic design; subjects instructed to use test material
subjects reported perceived discomfort
daily in the morning as a facial cleanser, twice weekly in and/or irritation, including
the evening as an exfoliating scrub, twice weekly in theburning/stinging and/or
evening as a purifying mask, and 3 times weekly in theredness/dryness while using the test
evening as a facial cleansermaterial; 6/8 subject responses were
not considered related to the use of thetest material and 2/8 subject responses
were not sufficient intensity to warrant
discontinuation of product
SENSITIZATION
IN VITRO
Not reported
KeratinoSens™
KeratinoSens™ assay (validated by ECVAM); 12
Not a sensitizer; test material weakly
cells
concentrations in 3 repetitions, in 3 replicates (details not toxic to cells
reported); luciferase induction and cellular viability
determined after 48 h incubation time
ANIMALNot reported
Guinea pigs;
Buehler test; no further details provided
Non-sensitizing
number/sex notprovided
5% (w/v) for
10 guinea pigs/sex Skin sensitization study in accordance with OECD TG
Negative for sensitization; no positive
intradermal injection;
406; no further details provided
skin responses at 24 or 48 h post-patch
concentration details
removal at challenge; no clinical signs
not provided for
during treatment
topical induction orchallenge; topicaldose was 100 mg test
material in 0.2 ml
vehicle
500 mgrabbits (no further
details)

Reference

39

28

40

41

42

39

7

28

Distributed for Comment Only -- Do Not Cite or Quote
Table 6. Dermal irritation and sensitization studies
Test Article

VehicleConcentration/Dose

Foot mask containing 3.5%
Bentonite

As supplied

0.2 g

Clay mask containing 3.8%
Bentonite

As supplied

0.1 - 0.15 g

Face cream containing 7.5%
Bentonite

As supplied

0.1 - 0.15 g;volatilized for 30-90
min prior toapplication

Lip product containing 14.5%
KaolinAs supplied

0.1 - 0.15 g

Clay mask containing 14.5%
KaolinNeat

0.1 mlClay mask containing 40% Kaolin As supplied

0.1 - 0.15 g

Sunscreen containing 1.75%
Bentonite

0.2 mlAs supplied

Test Population

Procedure

HUMAN
102 subjects
HRIPT under occlusive patches; induction patch appliedon the back for 9 total applications; 10-15 d non-treatment
period followed by challenge patch applied to naïve siteand scored at 48 h and 72 h post-application; patch was ~2 cm2108 subjects; 25% HRIPT under semi-occlusive patches; induction patchwith self-perceived applied on the back for 9 total applications; after a 2-wk
sensitive skinnon-treatment period, challenge patch applied to naïve siteand scored at 24 h and 72 h post-application; patch was ~2 cm2 and contained ~ 25 - 38 mg/cm2 test material
52 subjects
HRIPT under occlusive patches; induction patch appliedon the back for 9 total applications; after a 2-wk nontreatment period, challenge patch applied to naïve site andscored at 24 h and 72 h post-application; no further details
on patches provided
54 subjects
HRIPT under occlusive patches; induction patch appliedon the back for 9 total applications; after a 2-wk nontreatment period, challenge patch applied to naïve site andscore at 24 h and 72 h post-application; patch contained ~25 - 38 mg/cm2 test material
103 subjects
HRIPT under occlusive patches; induction patch appliedon the back or upper arm ;after a 10-15 d non-treatment
period, challenge patch applied to naïve site and scored at
48 and 72 h post-application; material was applied to a 2 x
2 cm2 Webril pad
51 subjects

Results

Reference

No dermal sensitization; no adverse
events reported

45

No dermal irritation or sensitization

43

No dermal irritation or sensitization

44

No dermal irritation or sensitization46

Not sensitizing; moderate erythema at
the first induction in one subject
mildly progressed through theinduction period to erythema andedema with papules; no other adverse
events reported during study
No dermal irritation or sensitization

48

HRIPT under occlusive patches; induction patch appliedon the back for 9 total applications; after a 2-wk nontreatment period, challenge patch applied to naïve site andscored at 24 h and 72 h post-application; no further details
on patches provided
PHOTOSENSITIZATION
HUMAN
23 subjects
Photoallergy test under occlusive patch; on day 1, subjects Not a photosensitizer
received test material on 2 sites on the back for 24 h, after
which, subjects received a total of 6 applications (twice
weekly) on the back; 24 h after application, one site wasirradiated with UVB + UVA with full Xenon lamp
spectrum, other site was non-irradiated control; after a
non-treatment period of 10-17 d, challenge patches onnaïve sites were placed and one site was irradiated with 6
J/cm2 UVA and ½ the minimal erythemal dose of UVB;
sites were evaluated at 24, 48, and 72 h after irradiation

47

49

Distributed for Comment Only -- Do Not Cite or Quote

REFERENCES
1. Andersen F, (ed),. 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. Int J Toxicol. 2003;22(Suppl 1):37-102.
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Accessed 01/07/2022.
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Burnett CL, Bergfeld WF, Belsito DV, et al. Amended Safety Assessment of Synthetically-Manufactured Amorphous
Silica and Hydrated Silica as Used in Cosmetics. Washington, DC. 2019. (Available from the Cosmetic Ingredient
Review.: https://www.cir-safety.org/ingredients.)

4.

Burnett CL, Bergfeld WF, Belsito DV, et al. Amended Safety Assessment of Silicates as Used in Cosmetics.
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5. U.S. Pharmacopeial Convention. Food Chemicals Codex. 12th ed. Baltimore, MD: United Book Press, Inc.; 2022.
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Care Products Council on April 25, 2022.
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Council on May 11, 2022.
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Products Council on March 30, 2022.
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on January 16, 201910.

Malvern. 2018. Analyse: Bentonite. Unpublished data submitted by the Personal Care Products Council on January 16,
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Spectrum. Safety Data Sheet. https://www.spectrumchemical.com/media/sds/H1406_AGHS.pdf. Accessed
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Crafter's Choice. Safety Data Sheet: Crafter's ChoiceTM White Kaolin Clay. https://www.crafterschoice.com/PDFs/ProductDocs/2700-SDS.pdf. Accessed 08/25/2022.

15.

Rustic Escentuals. Safety Data Sheet. https://www.rusticescentuals.com/SDS/KaolinClaySDS.pdf. Accessed
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Registration Program - Frequency of Use of Cosmetic Ingredients. College Park, MD. 2022. (Obtained under theFreedom of Information Act from CFSAN; requested as "Frequency of Use Data" January 4, 2022; received January
11, 2022.)
17.

Personal Care Products Council. 2022. Concentration of Use by FDA Product Category: Clays. Unpublished datasubmitted by the Personal Care Products Council on July 5, 2022.

18. Nourizadeh H, Bakhshayesh A. 2020. Nanoclay-based Products Across Global Markets: Applications and Properties.
Lund, Sweden: StatNano Publications.

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19.

European Commission. Cosing database; following Cosmetic Regulation (EC) No. 1223/2009
http://ec.europa.eu/growth/tools-databases/cosing/. .Last updated 2020. Accessed 01/10/2022.

20.

Scientific Committee on Consumer Safety (SCCS). Addendum to the scientific opinion SCCS/1613/19 on the safety ofaluminium in cosmetic products (lipstick) - Submission II. 2021. SCCS/1626/20.
https://ec.europa.eu/health/sites/default/files/scientific_committees/consumer_safety/docs/sccs_o_248.pdf. Accessed
01/25/2022.

21. Australian Government Department of Health. Australian Industrial Chemicals Introduction Scheme (AICIS).
https://www.industrialchemicals.gov.au/chemical-information. Accessed 01/10/2022.
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Drug Deliv. 2021;18(6):695-714.
23.

Bumbudsanpharoke N, Ko S. Nanoclays in food and beverage packaging. Journal of Nanomaterials.
2019;2019(Article ID 8927167).

24. Kasmani JE, Samariha A. Effects of montmorillonite nanoclay on the properties of chemimechanical pulping paper.
BioResources. 2021;16(3):6281-6291.
25.

Mousavi S, Bhojaraju C, Ouellet-Plamondon C. Clay as a Sustainable Binder for Concrete - A Review. Construction
Materials. 2021;1(3):134-168.

26.

Matar H, Guerreiro A, Piletsky S, Price S, Chilcott R. Preliminary evaluation of military, commercial and novel skindecontamination products against a chemical warfare agent simulant (methyl salicylate). Cutan Ocul Toxicol.
2016;35(2):137-144.

27. Hanif M, Jabbar F, S. S, G. A, A. F, M. A. Halloysite nanotubes as a new drug-delivery system: a review. Clay
Minerals. 2016;51:469–477.
28. Anonymous. 2022. Summary information French Velay Green Clay (ingredient tested as described in the Agile du
Velay technical data sheet for Velay Green Clay). Unpublished data submitted by the Personal Care Products
Council on March 30, 2022.
29.

Maisanaba S, Gutiérrez-Praena D, Puerto M, et al. Effects of the subchronic exposure to an organomodified clay
mineral for food packaging applications on Wistar rats. Appl Cly Sci. 2014;95:37-40.

30. Afriyie-Gyawu E, Mackie J, Dash B, et al. Chronic toxicological evaluation of dietary NovaSil clay in SpragueDawley rats. Food Addit Contam. 2005;22(3):259-269.
31.

Maisanaba S, Prieto A, Jordá-Beneyto M, Aucejo S, Jos A. Cytotoxicity and mutagenicity assessment of organomodified clays potentially used in food packaging. Toxicol In Vitro. 2015;29(6):1222-1230.

32.

Sharma AK, Schmidt B, Frandsen H, Jacobsen NR, Larsen EH, Binderup M-L. Genotoxicity of unmodified andorgano-modified montmorillonite. Mutat Res. 2010;700:18-25.

33.

Maisanaba S, Hercog K, Filipic M, Jos A, Zegura B. Genotoxic potential of montmorillonite clay mineral andalteration in the expression of genes involved in toxicity mechanisms in the human hepatoma cell line HepG2. J
Hazard Mater. 2016;304:425-433.

34. Geh S, Shi T, Shokouhi B, et al. Genotoxic potential of respirable bentonite particles with different quartz contents andchemical modifications in human lung fibroblasts. Inhal Toxicol. 2006;18(6):405-412.
35.

Sharma AK, Mortensen A, Schmidt B, et al. In-vivo study of genotoxic and inflammatory effects of the organomodified Montmorillonite Cloisite 30B. Mutat Res. 2014;770:66-71.

36. International Agency for Research on Cancer (IARC). 1997. Silica, Some Silicates, Coal Dust and para-Aramid
Fibrils. Vol 68. Lyon, France: World Health Organization.

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37.

California Office of Environmental Health Hazard Assessment (OEHHA). The Proposition 65 List.
https://oehha.ca.gov/proposition-65/proposition-65-list. Accessed 01/25/2022.

38.

Paydar S, Noorafshan A, Dalfardi B, et al. Structural alteration in dermal vessels and collagen bundles following
exposure of skin wound to zeolite-bentonite compound. J Pharm. 2016;2016:5843459.

39. Anonymous. 2022. Dermal irritation and sensitization data - Montmorillonite (ingredient tested contains 38%
Montmorillonite). Unpublished data submitted by the Personal Care Products Council on April 29, 2022.
40. Anonymous. 2012. A 14-day cumulative irritation assay (product contains 1.75% Bentonite). Unpublished datasubmitted by the Personal Care Products Council on April 25, 2022.
41. Anonymous. 2003. Human patch test (maks contains 8% Bentonite). Unpublished data submitted by the Personal Care
Products Council on April 25, 2022.
42. Anonymous. 2017. Clinical use test results of a 5 in 1 facial cleanser (containing 2% Bentonite and 2% Kaolin).
Unpublished data submitted by the Personal Care Products Council on April 25, 2022.
43. Anonymous. 2018. Clinical safety evaluation repeated insult patch test of a clay mask containing 3.8% Bentonite.
Unpublished data submitted by the Personal Care Products Council on April 4, 2022.
44. Anonymous. 2004. Clinical saftey evaluation: Repeated insult patch test (face cream contains 7.5% Bentonite).
Unpublished data submitted by the Personal Care Products Council on April 26, 2022.
45. Anonymous. 2019. Repeated insult patch test (product contains 3.5% Bentonite). Unpublished data submitted by the
Personal Care Products Council on April 25, 2022.
46. Anonymous. 2016. Clinical safety evaluation repeated insult patch test of a lip product containing 14.498% Kaolin.
Unpublished data submitted by the Personal Care Products Council on April 4, 2022.
47. Anonymous. 1997. Clinical safety evaluation: Repeated insult patch test (clay mask contains 40% Kaolin).
Unpublished data submitted by the Personal Care Products Council on April 26, 2022.
48.

TKL Research. 2004. Repeated insult patch study (clay mask with 14.5% Kaolin). Unpublished data submitted by the
Personal Care Products Council on August 17, 2022.

49. Anonymous. 2017. Photoallergy study (product contains 1.75% Bentonite). Unpublished data submitted by the
Personal Care Products Council on April 25, 2022.
50. Institute for In Vitro Sciences I. 2004. Tissue equivalent assay with EpiOcularTM cultures (clay mask with 14.5%
Kaolin). Unpublished data submitted by the Personal Care Products Council on August 17, 2022.
51. Wang J-S, Luo H, Billam M, et al. Short-term safety evaluation of processed calcium montmorillonite clay (NovaSil)in humans. Food Addit Contam. 2005;22(3):270-279.
52. National Institute for Occupational Safety and Health (NIOSH). NIOSH Pocket Guide to Chemical Hazards: Kaolin.
https://www.cdc.gov/niosh/npg/npgd0364.html. Accessed 01/13/2022.
53.

Maxim L, Niebo R, McConnell E. Bentonite toxicology and epidemiology - a review. Inhal Toxicol. 2016;28(13):591617.

Distributed for Comment Only -- Do Not Cite or Quote

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 Zeolite1

This report reviews the safety of Aluminum, Calcium, Lithium
Magnesium, Lithium Magnesium Sodium, Magnesium Aluminum,
Magnesium, Sodium Magnesium, and Zirconium Silicates, Magnesium Trisilicate, Attapulgite, Bentonite, Fuller’s Earth, Hectorite,
Kaolin, Montmorillonite, Pyrophyllite, and Zeolite as used in cosmetic formulations. The common aspect of all these claylike ingredients is that they contain silicon, oxygen, and one or more metals.
Many silicates occur naturally and are mined; yet others are produced synthetically. Typical cosmetic uses of silicates include abrasive, opacifying agent, viscosity-increasing agent, anticaking agent,emulsion stabilizer, binder, and suspending agent. Clay silicates (silicates containing water in their structure) primarily function as adsorbents, opacifiers, and viscosity-increasing agents. Pyrophyllite
is also used as a colorant. The International Agency for Research on
Cancer has ruled Attapulgite fibers >5 µm as possibly carcinogenic
to humans, but fibers <5 µm were not classified as to their carcinogenicity to humans. Likewise, Clinoptilolite, Phillipsite, Mordenite,
Nonfibrous Japanese Zeolite, and synthetic Zeolites were not classified as to their carcinogenicity to humans. These ingredients are
not significantly toxic in oral acute or short-term oral or parenteral
toxicity studies in animals. Inhalation toxicity, however, is readilydemonstrated in animals. 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.
Magnesium Aluminum Silicate was a weak primary skin irritantin rabbits and had no cumulative skin irritation in guinea pigs. No
gross effects were reported in any of these studies. Sodium Magnesium Silicate had no primary skin irritation in rabbits and had no
cumulative skin irritation in guinea pigs. Hectorite was nonirritating to the skin of rabbits in a Draize primary skin irritation study.
Magnesium Aluminum Silicate and Sodium Magnesium Silicate

Received 4 December 2002; accepted 18 March 2003.
1
Reviewed by the Cosmetic Ingredient Review Expert Panel. This
report was prepared by Amy R. Elmore, former Scientific Analyst andWriter. Address correspondence to F. Alan Andersen, Cosmetic Ingredient Review Director, 1101 17th Street, NW, Suite 310, Washington,
DC 20036, USA.
International Journal of Toxicology, 22(Suppl. 1):37–102, 2003
c Cosmetic Ingredient Review
Copyright °ISSN: 1091-5818 print / 1092-874X online
DOI: 10.1080/10915810390204890

caused minimal eye irritation in a Draize eye irritation test. Bentonite caused severe iritis after injection into the anterior chamberof the eyes of rabbits and when injected intralamellarly, widespreadcorneal infiltrates and retrocorneal membranes were recorded. In
a primary eye irritation study in rabbits, Hectorite was moderately irritating without washing and practically nonirritating to
the eye with a washout. Rats tolerated a single dose of Zeolite A
without any adverse reaction in the eye. Calcium Silicate had no
discernible effect on nidation or on maternal or fetal survival in
rabbits. Magnesium Aluminum Silicate had neither a teratogenic
nor adverse effects on the mouse fetus. Female rats receiving a 20%
Kaolin diet exhibited maternal anemia but no significant reduction
in birth weight of the pups was recorded. Type A Zeolite produced
no adverse effects on the dam, embryo, or fetus in either rats or
rabbits at any dose level. Clinoptilolite had no effect on female rat
reproductive performance. These ingredients were not genotoxic in
the Ames bacterial test system. In primary hepatocyte cultures, theaddition of Attapulgite had no significant unscheduled DNA synthesis. Attapulgite did cause significant increases in unscheduled
DNA synthesis in rat pleural mesothelial cells, but no significant increase in sister chromosome exchanges were seen. Zeolite particles(<10 µm) produced statistically significant increase in the percentage of aberrant metaphases in human peripheral blood lymphocytes and cells collected by peritoneal lavage from exposed mice.
Topical application of Magnesium Aluminum Silicate to humanskin daily for 1 week produced no adverse effects. Occupational
exposure to mineral dusts has been studied extensively. Fibrosis
and pneumoconiosis have been documented in workers involvedin the mining and processing of Aluminum Silicate, Calcium Silicate, Zirconium Silicate, Fuller’s Earth, Kaolin, Montmorillonite,
Pyrophyllite, and Zeolite. The Cosmetic Ingredient Review (CIR)
Expert Panel concluded that the extensive pulmonary damage inhumans was the result of direct occupational inhalation of the dusts
and noted that lesions seen in animals were affected by particle size,
fiber length, and concentration. The Panel considers that most of
the formulations are not respirable and of the preparations that are
respirable, the concentration of the ingredient is very low. Even so,
the Panel considered that any spray containing these solids should
be formulated to minimize their inhalation. With this admonition to
the cosmetics industry, the CIR Expert Panel concluded that these
ingredients are safe as currently used in cosmetic formulations.

37

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38

COSMETIC INGREDIENT REVIEWThe Panel did note that the cosmetic ingredient, Talc, is a hydrated
magnesium silicate. Because it has a unique crystalline structurethat differs from ingredients addressed in this safety assessment,
Talc is not included in this report.

INTRODUCTION
Various silicates and silicate clays are used in cosmetics,
largely for their adsorbent, anticaking, bulking, and other similar properties. They are created synthetically in some cases, e.g.,
Lithium Magnesium Silicate, or are refined from naturally occurring minerals, e.g., Magnesium Aluminum Silicate. In either
case, variations in composition occur. Thus the Zeolite groupof hydrated aluminosilicates has forms that are crystalline or
fibrous, and contain interchangeable cations.
This report reviews the safety of these ingredients. Because
the issues of safety are likely to be similar, many ingredients
have been grouped. Although there are not data on each andevery ingredient, it is expected that the data will be broadly applicable among the following ingredients: Aluminum Silicate(CAS no. 1327-36-2); Calcium Silicate (CAS no. 1344-95-2);
Magnesium Aluminum Silicate (CAS no. 12199-37-0, 132743-1, 12511-31-8); Magnesium Silicate (CAS no. 1343-88-0);
Magnesium Trisilicate (CAS no. 14987-04-3); Sodium Magnesium Silicate; Zirconium Silicate (CAS no. 14940-68-2); andthe silicate clays/clay minerals: Attapulgite (CAS no. 1337-764, 12174-11-7); Bentonite (CAS no. 1302-78-9); Fuller’s Earth(CAS No. 8031-18-3); Hectorite (CAS no. 12173-47-6); Kaolin(CAS no. 1332-58-7); Lithium Magnesium Silicate; Lithium
Magnesium Sodium Silicate (CAS no. 53320-86-8); Montmorillonite (CAS no. 1318-93-0); Pyrophyllite (CAS no. 1226978-2); and Zeolite (CAS no. 1318-02-1) used in cosmetics.
It is important to note that the cosmetic ingredient, Talc,
is not included in this safety assessment. Talc is a hydrated
magnesium silicate with the CAS no. 14807-96-6, but it should
not be confused with any of the silicates in this report. Talc isdifferentiated by its definition, a hydrated magnesium silicate,and its unique crystalline form.
The safety of Quaternium-18 Hectorite and Quaternium-18
Bentonite have been previously reviewed by the Cosmetic Ingredient Review (CIR) Expert Panel; the final conclusion indicatedthat “Quaternium-18 Hectorite and Quaternium-18 Bentonite
are safe as cosmetic ingredients in the present practices of use
and concentration” (CIR 1980).

of which are natural Zeolites (IARC 1997). Even though these
Zeolites are considered to be a group, the formulas of the mostcommon are listed in tabular form in Table 2 so the reader canunderstand the diversity in this category.
Physical and Chemical Properties
In alphabetical order according to the cosmetic ingredientname as specified in the International Cosmetic Ingredient Dictionary and Handbook (Wenninger et al. 2000), Table 3 provides information on the various synonyms used to describe eachcosmetic ingredient, lists the available information on physicalproperties, and, if available, provides the specifications for thecosmetic grade of the ingredient.
Clay Structure
According to Grim (1967), clays in general have atomic lattices consisting of two structural units. One unit consists of
two sheets of closely packed oxygens or hydroxyls as shownin Figure 1. Aluminum, iron, or magnesium atoms are embedded within these sheets in octahedral coordination, so that they
are equidistant from the oxygen or hydroxyl groups.
The second unit is composed of silica tetrahedrons as shownin Figure 2. Assuming there are no distortions in each tetrahedron, a silicon atom is equidistant from four oxygens or hydroxyls, if needed to balance the structure, arranged in the form ofa tetrahedron with a silicon atom in the center. The silica tetrahedral groups are arranged in a hexagonal network, which isrepeated infinitely to form a sheet of composition Si4 O6 (OH)4 .
The tips of the tetrahedrons all point in the same direction andthe bases are all in the same plane. Substantial distortion of theseunits occurs in order to fit into determined unit-cell dimensionsof minerals (Grim 1967).
Attapulgite
The general attributes of structure and composition of theminerals are not very well known. The structurally important element is the amphibole double silica chain oriented with its long
direction parallel to the c axis as shown in Figure 3. Attapulgite

CHEMISTRY
Given the large number of ingredients, a tabular presentationof basic information concerning the chemical description has
been provided (Table 1).
Zeolites
The Zeolite group is very diverse. Over 100 structural typesof Zeolites, both natural and synthetic, have been reported, 40

FIGURE 1(a) Single octahedral unit; (b) Sheet of units (taken from Grim
1967 with permission).

Distributed for Comment Only -- Do Not Cite or Quote

39

SILICATESTABLE 1
Chemical formulas and compositions of Silicates and Silicate Clays used in cosmetics
Ingredient

Description

Al2 O3 · SiO2
Complex inorganic salt that has a composition of consisting generallyof 1 mole of alumina and 1 to 3 moles of silica
Calcium Silicate
Varying CaO and SiO2
Hydrous or anhydrous silicate with varying proportionsof calcium oxide and silica
Magnesium Aluminum Al2 MgO8 Si2
Silicate
Complex silicate refined from naturally occurring minerals
Magnesium Silicate
MgO · SiO2 · xH2 O
Inorganic salt of variable composition
Magnesium Trisilicate 2MgO3 · SiO2 · xH2 O
Inorganic compound
Zirconium Silicate
ZrSiO4
Inorganic compound
Zircon sand or flour; specially sized grades of the mineral zircon—anaturally occuring zirconium silicate
Attapulgite[Mg(Al0.5–1 Fe0–0.5 ]Si4 O10 (OH) · 4H2 O
Variety of Fuller’s Earth (q.v.) found typically near Attapulgas,
Georgia. It is characterized as having a chain structure rather thanthe usual sheet structure of other clays
Hydrated magnesium aluminum silicate with magnesium partiallyreplaced by aluminum, or to a lesser extent, ironPurified native magnesium aluminum silicate
Bentonite
Al2 O3 · 4SiO · 2H2 Oa (empirical formula)
Na0.33 [Al1.67 Mg0.33 ]Si4 [OH]2
Native hydrated colloidal aluminum silicate clay
Commercial term for clays containing montmorillonite type minerals
formed by the alteration of volcanic ash
Fuller’s Earth
No specific formula
Nonplastic variety of kaolin containing an aluminum magnesium
silicate
Porous colloidal aluminum silicate, a catch-all phrase for clay or otherfine-grained earthy material suitable for use as an absorbent andbleachHectorite
Na0.67 (Mg,Li)6 Si8 O20 (OH,F)4 a
Na0.33 [Mg2.67 Li0.33 ]Si4 O10 [OH]2Montmorillonite mineral that is the principle constituent
of bentonite clays
Fluorine-bearing magnesium rich montmorillonite
Almost a complete substitution of aluminum in the lattice structureof bentonite by magnesium in hectorite and the presenceof lithium and flourine
Kaolin/Kaolinite
Al2 O3 · 2SiO2 · 2H2 O
Native hydrated aluminum silicate
Kaolinite is the mineral that characterizes most Kaolins
Lithium Magnesium
No specific formula
Silicate
Synthetic clay consisting of mainly lithium and magnesium silicates
Aluminum Silicate

Reference
Wenninger et al. 2000
Wenninger et al. 2000
Wenninger et al. 2000
Wenninger et al. 2000
Budavari 1989
Wenninger et al. 2000
Wenninger et al. 2000
Wenninger et al. 2000
Wenninger et al. 2000
Wenninger et al. 2000
Wenninger et al. 2000
Wenninger et al. 2000
American Minerals, Inc. 1998
IARC 1997
Wenninger et al. 2000

IARC 1997
Barr and Arnista 1957
Informatics, Inc. 1974
Rheox Inc. 1999
Wenninger et al. 2000
Gamble 1986
Wenninger et al. 2000
Wenninger et al. 2000
Gamble 1986

Budavari 1989
Rheox Inc. 1999
Wenninger et al. 2000
Grim 1972
United States Pharmacopeial
Convention, Inc. 1994
Wenninger et al. 2000
Wenninger et al. 2000
Ross and Kerr 1931
Wenninger et al. 2000
Wenninger et al. 2000
(Continued on next page)Distributed for Comment Only -- Do Not Cite or Quote

40

COSMETIC INGREDIENT REVIEWTABLE 1
Chemical formulas and compositions of Silicates and Silicate Clays used in cosmetics (Continued)
Ingredient

Description

Lithium Magnesium
Sodium Silicate

No specific formula
Synthetic clay consisting mainly of lithium, magnesium, andsodium silicates
+
+
+
2+
2+
R+
0.33 (Al,Mg)2 Si4 O10 (OH)2 , where R = Na , K , Mg , or Ca
Complex aluminum/magnesium silicate clay
Term used to describe a group of minerals with an expanding lattice,
except vermiculite and also a specific mineral with a high-alumina
end member of the montmorillonite group with some slight
replacement of Al3+ by Mg++ and substantially no replacementof Si4+ by Al3+
Al2 O3 · 4SiO · 2H2 O
Naturally occurring mineral substance consisting predominantlyof a hydrous aluminum silicate
No specific formula
Synthetic silicate clay with a composition mainly of magnesium andsodium silicate
M2/n O · Al2 O3 · ySiO2 · xH2 O(M = a group IA or IIA element;n = cation valence; y = 2 or greater; x = the number of watermolecules within the molecule)
Hydrated alkali aluminum silicate
Group of hydrated, crystalline aluminosilicates containing
exchangeable cations of group IA and IIA elements such as sodium,
potassium, magnesium, and calcium

Montmorillonite

Pyrophyllite

Sodium Magnesium
Silicate
ZeoliteTABLE 2
Zeolites (IARC 1997)
Zeolite

CAS no.

Chemical formula

Clinoptilolite 12173-10-3 Not given(general)
12271-42-0 Na(AlSi5 O12 · xH2 O)
67240-23-7 AlNaH16 (SiO4 · 4H2 O)
Mordenite
12173-98-7 Not given(general)
12445-20-4 AlNaH6 (SiO3 )566732-10-3 Al2 CaH12 (SiO3 )10 · H2 O
68652-75-5 Na(AlSi5 O12 )Phillipsite
12174-18-4 Not given(general)
61027-84-7 CaK[Al3 O(SiO3 )5 ] · 6H2 O66733-09-3 AlNa(SiO4 ) · 6H2 O
Zeolite A
68989-22-0 Na12 [(AlO2 )12 (SiO2 )12 ] · 27H2 O
Zeolite X
68989-23-1 Na86 [(AlO2 )86 (SiO2 )106 ] · 264H2 O
Zeolite Y
Not specified Na56 [(AlO2 )56 (SiO2 )136 ] · 250H2 O
Zeolite L
Not specified K9 [(AlO2 )9 (SiO2 )27 ] · 22H2 O
ZSM-5
79982-98-2 (NaTPA)3 [(AlO2 )3 (SiO2 )93 ] ·16H2 O∗∗TPA = tetrapropylammonium.

Reference
Wenninger et al. 2000
Wenninger et al. 2000
Budavari 1989
Wenninger et al. 2000
Grim 1972

Wenninger et al. 2000
Wenninger et al. 2000
Wenninger et al. 2000
Wenninger et al. 2000
IARC 1997

Wenninger et al. 2000
IARC 1997

consists of double silica chains situated parallel to the c axis
with the chains linked together through oxygens at their longitudinal edges. Tetrahedral apexes in successive chains point in
the opposite direction. The linked chains form a kind of doubleribbed sheet with two rows of tetrahedral apexes at alternate
intervals in the top and bottom of the sheets. The ribbed sheets
are arranged so that the apex oxygens of successive sheets point
together and are held together by aluminum and/or magnesiumin octahedral coordination between the apex oxygens of successive sheets. Chains of water molecules run parallel to the c axis
and fill the interstices between the amphibole chains. Aluminum
substitutions for silicon is considered probable (Grim 1967).

FIGURE 2(a) Single tetrahedral unit; (b) Sheet of units (taken from Grim
1967 with permission).

Distributed for Comment Only -- Do Not Cite or Quote

41

SILICATESTABLE 3
Synonyms for, physical properties of, and specifications for Silicates and Silicate Clays used in cosmetics
Item
Synonyms

Form/description

Molecular weight
Density
Solubility

Description
Aluminum Silicate
Anhydrous aluminum silicate, china clay, natural aluminum silicate,pyrophyllite, synthetic aluminum silicate, willinite
KaolinAluminosilicate
Generally consisting of 1 mole of alumina and 1 to 3 moles of silica
Four naturally occurring minerals (andalusite, cyanite, sillimainte,mullite); other associated minerals: anauxite, dickite, kaolinite,kochite, newtonite, pyrophyllite, takizolite, termierite, and ton
Variable: ranging from 162.05 to 426.05 Da
Variable: 3.156, 3.247
Insoluble in water

Synonyms
Form/description

Calcium Silicate
Silicic acid, calcium salt
Hydrous or anhydrous silicate with varying proportions ofcalcium oxide and silica
White or slightly cream colored free-flowing powder
116.16 Da
Insoluble in water
8.0–10.0 (aqueous slurry)
Magnesium Aluminum Silicate
Aluminum magnesium silicate, magnesium aluminosilicate,complex colloidal, Carrisorb, Gelsorb, VEEGUM
Aluminosilicic acid, magnesium salt, aluminum magnesium silicate
Complex silicate refined from naturally occurring minerals
Off-white to creamy white small flakes or micronized powder262.4 Da
Insoluble in water, alcohol, and organic solvents
9.0–10.0 (5% aqueous solution)
225–2200 mPa
Arsenic (as As), 3 ppm maximum
Lead (as Pb), 10 ppm maximum
Magnesium Silicate
Silicic acid, magnesium salt (1:1)
Fine, white, odorless, tasteless, powder, free from grittinessSolubility

Insoluble in water and alcohol

CTFA specifications

Arsenic (as As), 3 ppm maximum
Lead (as Pb), 20 ppm maximum

Synonyms
Form/description

Molecular weight
SolubilitypH
Synonyms

Form/description
Molecular weight
Solubility
pH
Viscosity
CTFA specifications

Synonyms
Form/description

Magnesium Trisilicate
Silicic acid, magnesium salt (1:2)
Fine, white, odorless, tasteless powder, free form grittinessSolubility

Insoluble in water and alcohol

Synonyms
Form/description

Sodium Magnesium Silicate
Synthetic sodium magnesium silicate
Synthetic silicate clay with a composition mainly of magnesium andsodium silicate

Reference
Wenninger et al. 2000
Budavari 1989
Syracuse Research Corp. 1974
Wenninger et al. 2000
Budavari 1989

Lide 1993
Lide 1993
Syracuse Research Corp. 1974
Wenninger et al. 2000
Wenninger et al. 2000
Budavari 1989
Lide 1993
Budavari 1989
Budavari 1989
Palmieri 1994
Wenninger et al. 2000
Wenninger et al. 2000
Palmieri 1994
Budavari 1989
Palmieri 1994
Nikitakis and McEwen 1990b
Palmieri 1994
Nikitakis and McEwen 1990a
Nikitakis and McEwen 1990a
Wenninger et al. 2000
United States Pharmacopeial
Convention, Inc. 1994
United States Pharmacopeial
Convention, Inc. 1994
Nikitakis and McEwen 1990a
Nikitakis and McEwen 1990a
Wenninger et al. 2000
United States Pharmacopeial
Convention, Inc. 1994
United States Pharmacopeial
Convention, Inc. 1994
Wenninger et al. 2000
Wenninger et al. 2000
(Continued on next page)Distributed for Comment Only -- Do Not Cite or Quote

42

COSMETIC INGREDIENT REVIEWTABLE 3
Synonyms for, physical properties of, and specifications for Silicates and Silicate Clays used in cosmetics (Continued)
Item
Synonyms

Form/description

Molecular weight
Solubility
DensitypH
CTFA specifications

Synonyms

Form/description

Density
Solubility

Synonyms

Form/description

Molecular weight
Solubility
pH
Particle size
Color
Swelling ability
Iron
Synonyms
Form/description

Description
Zirconium Silicate
Silicic acid, zirconium salt (1:1)
Zircon, zirconium orthosilicate
Zirconium (IV) silicate (1:1)
Bipyramidal crystals, colorless unless has impurities andradioactive bombardment
Red or various colored crystals
183.31 Da
Insoluble in alcohol, aqueous solution, and alkali
4.56
6–7.5 (10% aqeous slurry)
Arsenic (as As), 3 ppm maximum
Lead (as Pb), 20 ppm maximum
Attapulgite
Activated attapulgite, Attaclay, Attagel, Attasorb, Min-u-gel,palygorskit, Permagel, Zeogel
Palygorskite
Variety of Fuller’s Earth; characterized by a chain structure rather
than the sheet structure of other clay minerals
White, gray, or transparent, dull, elongated, lath-shaped crystals inbundles that comprise thin sheets of minute interlaced fibers;
surface is protonated and hydrated
2.2
Insoluble in water
Bentonite
CI 77004, soap clay
Albagel Premium USP 4444, Bentonite magma, Hi-gel, Imvite
I.G.B.A., Magbond, montmorillonite, Tixoton, Volclay, Wilkinite
BentoPharm, E558, mineral soap, soap clay, taylorite, Veegum HS,
wilkinite
Native hydrated colloidal aluminum silicate clay
Crystalline, claylike material, available as an odorless, palebuff or
cream to grayish-colored fine powder, which is free from grit
Dioctahedral
359.16 Da
Practically insoluble in ethanol, fixed oils, glycerin, propan-2-ol
and water
9.5–10.5 for a 2% aqueous solution
Mainly 50–150 µm along with 1–2 µm particles
0.8 × 0.8 × 0.01 µ
Grey to green
15×
2.3%
Fuller’s EarthEnglish Fuller’s earth
Nonplastic variety of kaolin
Sheet structure

Reference
Wenninger et al. 2000
Budavari 1989
Lewis 1993
Budavari 1989
Lewis 1993
Budavari 1989
Lide 1993
Lide 1993
American Minerals 1998
Nikitakis and McEwen 1990a
Nikitakis and McEwen 1990a
Registry of Toxic Effects
of Chemical Substances(RTECS) 1999
IARC 1997
Wenninger et al. 2000
IARC 1997

IARC 1997
United States Pharmacopeial
Convention, Inc. 1994
Wenninger et al. 2000
RTECS 1999
Belmonte 1994
Wenninger et al. 2000
Belmonte 1994
Rheox Inc. 1999
Belmonte 1994
Belmonte 1994
Belmonte 1994
Belmonte 1994
Rheox Inc. 1999
Rheox Inc. 1999
Rheox Inc. 1999
Rheox Inc. 1999
Wenninger et al. 2000
Wenninger et al. 2000
Gamble 1986
(Continued on next page)Distributed for Comment Only -- Do Not Cite or Quote

43

SILICATESTABLE 3
Synonyms for, physical properties of, and specifications for Silicates and Silicate Clays used in cosmetics (Continued)
Item
Synonyms
Form/description

Particle size
pH
Iron
Color
Swelling ability
Odor
Specific gravity
Synonyms

Form/description
Molecular weight
Solubility
Cation exchange capacity
CTFA specifications

Synonyms
Form/description

Synonyms
Form/description

Synonyms
Form/description
Cation exchange capacity
Synonyms
Form/description

Synonyms
Form/description
pH
Solubility

Description
Hectorite
Macaloid, Ben-A-Gel
Bentone and Bentone Gel
Translucent colorless mineral when mined and turns whitewhen dried
Tridecahedral
0.8 × 0.08 × 0.01 µ
8.5 (5% slurry)
0.2% (typical)
Light pink to tan; off-white
35×
None
2.65
KaolinBolbus Alba, China Clay, CI 77004, Kolite, Pigment White 19
Altowhites, Argilla, Bentone, China Clay, Emathlite, Fitrol, Glomax,
Hydrite, Kaopaous, Langford, Mcnamee, Parclay, Porcelin Clay,
Snow tex
Bolbus alba, China clay, white bole, argilla, terra alba, porcelin clay
White or yellowish white, earthy mass or white powder; unctous
when moist
Native hydrated aluminum silicate
258.2 Da
Insoluble in water, cold acids, or in alkali hydroxides
3–15 mEq/100 g
Arsenic (as As), 3 ppm maximum
Lead (as Pb), 20 ppm maximum
Lithium Magnesium Silicate
Silicic acid, lithium magesium salt
Synthetic silicate clay consisting mainly of lithium andmagnesium silicates
Lithium Magnesium Sodium Silicate
Magnesium lithium sodium silicate; silicic acid, lithium,magnesium, and sodium salt
Synthetic silicate clay consisting mainly of lithium, magnesium andsodium silicates
Montmorillonite
SmectiteComplex aluminum/magnesium silicate clay
80–150 mEq/100 g
Pyrophyllite
Pyrophyllite clay
Naturally occurring mineral—predominantly hydrous aluminumsilicate
Sodium Magnesium Silicate
Synthetic sodium magnesium silicate
Synthetic silicate clay with a composition mainly of sodium andmagnesium silicate
8.5–10.5 of 2% aqueous dispersion
Insoluble in organic solvents and disperses in water

Reference
Barr 1963
Rheox Inc. 1999
Barr 1963
Rheox Inc. 1999
Rheox Inc. 1999
Rheox Inc. 1999
Rheox Inc. 1999
Rheox Inc. 1999
Rheox Inc. 1999
Rheox Inc. 1999
Rheox Inc. 1999
Wenninger et al. 2000
RTECS 1999

Informatics, Inc. 1974
Budavari 1989
Wenninger et al. 2000
Budavari 1989
Budavari 1989
Carrol 1959
Nikitakis and McEwen 1990a
Nikitakis and McEwen 1990a
Wenninger et al. 2000
Wenninger et al. 2000

Wenninger et al. 2000
Wenninger et al. 2000

Grim 1972
Wenninger et al. 2000
Carrol 1959
Wenninger et al. 2000
Wenninger et al. 2000

Wenninger et al. 2000
Wenninger et al. 2000
Nikitakis and McEwen 1990b
Nikitakis and McEwen 1990b(Continued on next page)Distributed for Comment Only -- Do Not Cite or Quote

44

COSMETIC INGREDIENT REVIEWTABLE 3
Synonyms for, physical properties of, and specifications for Silicates and Silicate Clays used in cosmetics (Continued)
Item
Synonyms

Form/description

Description

Reference

ZeoliteAluminosilicates, Bacterkiller, CS100, Sitton, Zeokar, Zeolith,
Zeolum, Zeostar
Clinoptilotile, Mordenite, Phillipsite, Zeolite A, Zeolite X, ZSM-5,
Non-fibrous Japanese Zeolite
Crystalline, hydrated alkali-aluminum silicates

Wenninger et al. 2000
IARC 1997
Budavari 1989; Wenninger
et al. 2000

KaolinKaolin’s structure is composed of a single silica tetrahedral
sheet and a single alumina octahedral sheet combined in a unit sothat the tips of the silica tetrahedrons and one of the layers of theoctahedral sheet form a common layer as shown in Figure 4. All
the tips of the silica tetrahedrons point in the same direction andtoward the center of the unit made by the silica and octahedral
sheets. Composite octahedral-tetrahedral layers are formed dueto the similarity between the sheets a and b dimensions. The
common layer between the octahedral and tetrahedral groups
consists of two thirds of shared atoms between silicon and aluminum that become O instead of OH. Analyses of Kaolin haveshown there is little substitution within the lattice. In a small percentage of cases, iron and/or titanium has replaced aluminum.
This has only been seen in the relatively poor crystalline varietiesof Kaolin (Grim 1967).

FIGURE 3
Attapulgite structure (taken from Grim 1967 with permission).

FIGURE 4
Kaolin layer (taken from Grim 1967 with permission).

Smectites (Montmorillonites, Hectorite, and Bentonite)
Smectite units comprise of two silica tetrahedral sheets witha central alumina octahedral sheet as shown in Figure 5. All
tetrahedral tips point in the same direction and toward the centerof the unit. The tips of the tetrahedrons of each silica sheet andone of the hydroxyl layers of the octahedral sheet form a common
layer. As in Kaolin, the atoms common to both the tetrahedral
and octahedral layer become O instead of OH. These layers arecontinuous in the a and b directions and are stacked one above
the other in the c direction. As a consequence, O layers in theunits become adjacent and a very weak bond is created with thepossibility of cleavage. The preeminent feature of smectites isthe ability of water and other organic molecules to enter between
unit layers and expand in the c direction. Expansion propertiesare reversible; however, the structure is completely collapsed
by removal of interlayer polar molecules. Most smectites havesubstitutions within their lattices: aluminum or phosphorous forDistributed for Comment Only -- Do Not Cite or Quote
SILICATES

45

KaolinDeposits of Kaolin have been found in England, the UnitedStates, France, Czechoslovakia, Germany, and Japan (Informatics, Inc. 1974).
Pyrophyllite
Gamble (1986) reported Pyrophyllite being mined primarily
in North Carolina.
ZeoliteNatural Zeolites are mined in Japan, the United States,
Hungary, Bulgaria, Cuba, Italy, and South Africa (Roskill Informations Services Ltd. 1988).
Method of Manufacture
Aluminum Silicate
Aluminum Silicate is a naturally occurring mineral as well
as artificially produced. The naturally occurring Aluminum Silicate minerals are know as andalusite, sillimanite, and cyanite.
Natural Aluminum Silicate is mined from an ore and synthetic
Aluminum Silicate is formed by heating compositions of controlled proportions of silica, alumina, and alkalis under conditions to promote the specific structure (Syracuse Research Corp.
1981).

FIGURE 5
Smectite structure (taken from Grim 1967 with permission).
silicon in the tetrahedral coordination and/or magnesium, iron,zinc, nickel, lithium, etc. for aluminum in the octahedral sheet(Grim 1967).

Natural Occurrence of Clays
Aluminum Silicate
Natural Aluminum Silicates are reportedly being mined inIndia, California, North Carolina, and Georgia (Gamble 1986).

Attapulgite
Attapulgite is mined in 10 countries: Australia, China, France,
India, Russia, Senegal, South Africa, Spain, Turkey, and theUnited States (Informatics, Inc. 1974).

Bentonite
Large deposits of Bentonite have been discovered in Canada,
China, France, Germany, Great Britain, Greece, Hungary, Italy,
Japan, Mexico, New Zealand, North Africa, Poland, South
Africa, the former Soviet Union, and the United States (Informatics, Inc. 1974).

Attapulgite
Hevilin and Murray (1994) describe the mining process of Attapulgite as an opencast technique, stripping layers with heavymachines such as bulldozers, backhoes, and excavators. The
clay is then transported to a processing plant where crushing,drying, classification, and pulverizing takes place. High-heatdrying to remove water may occur to enhance absorbent
qualities.
Bentonite
The mined ore of Bentonite is processed to remove grit andnonswelling materials (Belmonte 1994).
KaolinIn a process described by Wells, Bhatt, and Flanagan (1985),
Kaolin is extracted from kaolinized granite by washing it out
with powerful and remote water hoses. The clay stream is thenpumped to the separation plant where sand and mica are removed. The purified clay is filtered when wet and then dried.
The very fine powder is formed by milling.
Magnesium Aluminum Silicate
Magnesium Aluminum Silicate is obtained from silicate oresof the montmorillonite group. The ores are blended with water toproduce a slurry, which is then processed to remove impurities
and separate out the colloidal fractions. Refined colloidal fractions are dried to form a small flake and then is microatomized
to form various powder grades (Palmieiri 1994).

Distributed for Comment Only -- Do Not Cite or Quote

46

COSMETIC INGREDIENT REVIEW

ZeoliteRoskill Informations Services Ltd. (1988) reported natural
Zeolites being recovered from deposits by selective opencast
or strip mining processes. The raw material is then processedby crushing, drying, powdering, and screening. Synthetic Zeolite synthesis requires the following conditions: reactive starting materials; a high pH; a low-temperature hydrothermal statewith concurrent low autogenous pressure at saturated water pressure; and a high degree of supersaturation of a large number ofcrystals.
Analytical Methods
Montmorillonite has been detected using far infrared spectra(Angino 1964). Bentonite and Kaolin are described by Angino(1964) using far infrared spectra and by Sadik (1971) using x-ray
diffraction. Attapulgite has been detected with the use of transmission or scanning electron microscope (Zumwalde 1976), andby means of x-ray powder diffraction analysis (Keller 1979). The
characterization of Hectorite was achieved through x-ray diffraction, infrared spectroscopy, and chemical analysis (Browne et al.
1980). Zeolites have been examined using scanning electron microscopy (Wright and Moatamed 1983; van Hoof and Roelofsen
1991) and x-ray diffraction (van Hoof et al. 1991). Magnetic angle spinning nuclear magnetic resonance (NMR) has confirmed
the structural breakdown of Fuller’s Earth (Drachman, Roch,and Smith, 1997).

IMPURITIES/COMPOSITION
Aluminum Silicate
Other minerals associated with natural Aluminum Silicatesare anauxite, dickite, kaolinite, kochite, mullite, newtonite, pyrophyllite, takizolite, terierite, and ton (Budavari 1989).
Attapulgite
Attapulgite commonly is found with smectites, amorphoussilica, chert, and other minerals (Bish and Guthrie 1993).
A typical composition is shown in Table 4 (Keller 1979).
Bentonite
The principle constituent is Montmorillonite. However, otherminerals such as illite, kaolinite, and nonargillaceous detrital
minerals can be present. Most Bentonites appear relatively pureand other mineral contributions rarely exceed 10%. Cristobalite
is often present. Montmorillonite compositions frequently varyeither in its lattice structure or in the exchangeable ions present(Informatics, Inc. 1974).
A typical composition is shown in Table 4 (Belmonte1994).
Fuller’s Earth
Principle deposits of Fuller’s Earth include Montmorillonite,
Bentonite, Attapulgite, and sepiolite (Gamble 1986).

TABLE 4Mineral composition of individual samples of Magnesium Aluminum Silicate, Attapulgite, Bentonite, Hectorite, Kaolinite,
and Montmorrillonite (Barr 1963)
Silicate clays analyzed
MineralMagnesium Aluminum Silicate(%)

Attaplugite(%)

Bentonite(%)

Hectorite(%)

Kaolinite(%)

Montmorillonite
(%)

SiO2
Al2 O3Fe2 O3
FeO
MgO
CaO
K2 O
Na2 O
TiO2
CO2
LiO2
F
MnO
ZnO
H2 O
Reference

61.1
9.3
—
0.9
13.7
2.7
0.3
2.9
0.1
1.8
—
—
—
—
7.2
Palmieri 1994

55.03
10.24
3.53
—
10.49
—
0.47
—
—
—
—
—
—
—
19.86
Keller 1979

59.92
19.78
—
2.96
1.53
0.64
0.57
20.6
—
—
—
—
—
—
Not reported
Belmonte 1994

55.86
0.13
0.03
—
25.03
Trace
0.10
2.68
—
—
1.05
5.96
—
—
12.14
Keller 1979

45.44
38.52
0.80
—
0.08
0.08
0.14
0.66
0.16
—
—
—
—
—
14.20
Keller 1979

51.14
19.76
0.83
—
3.22
1.62
0.11
0.04
—
—
—
—
Trace
0.10
22.80
Keller 1979

Distributed for Comment Only -- Do Not Cite or Quote
SILICATES

Hectorite
Principle impurities include calcite, dolomite, silica crystals,
and grit (Barr 1963). A typical composition is shown in Table 4(Keller 1979).
KaolinQuartz, mica, and feldspar are often found associated withthe crude mineral and is often removed through screening andelutriation (Informatics, Inc. 1974).
Ferreira and Freitas (1976) surveyed Kaolin for any potentially pathogenic organisms and a mean viable count. Pseudomonas aeruginosa, Salmonella typhosa, Escherichia coli,
Staphylococcus aureus, and Clostridium tetani were absent. The
mean viable count was 74 × 103 /6 M. The bacteria present were
mostly gram-positive aerobic spore-formers.
A typical composition is shown in Table 4 (Keller 1979).
Magnesium Aluminum Silicate
One trade-name group of products contain 1% to 6% by volume weight crystalline silica in the form of cristabalite; they alsocomment that a few grades may contain quartz as well (Kelse
1997).
A typical composition is shown in Table 4 (Palmeiri 1994).
Montmorillonite
A typical composition of Montmorillonite is shown in Table 4(Keller 1979).
ZeoliteValatina, Pylev, and Lemjasev (1994) analyzed the chemical compositions of five samples of Zeolite dusts taken frommines in Russia (Table 5). The benzo[a]pyrene content in thedusts of natural Zeolite tuffs (rock deposits) ranged from 0.0 to
3.6 µg/kg.

TABLE 5
Zeolite mine dust chemical analysis (Valatina, Pylev, andLemjasev 1994)
Dust sample

1

2

3

4

5

Molar ratio of SiO2 /Al2 O3
Zeolite (%)
Silicon dioxide (%)
Aluminum oxide (%)
Iron (III) oxide (%)
Magnesium oxide (%)
Calcium oxide (%)
Sodium oxide (%)
Benzo[a]pyrene

9.0

8.3

9.8

7.4

9.4

83
66.84
12.36
0.92
1.53
2.36
2.65
2.5

50.6
73
63
56
0
70.92 62.64 68.6
12.62 12.11 14.17 12.16
4
1.03
2.65
0.2
1.34
0.53
1.19
0.93
4.15
2.56
2.01
1.93
0.15
0.62
1.75
2
3.6
0.1
1.3
0

47

USE
Cosmetic
According to the European Cosmetic Directive (EU reference
no. 391 Annex II), Zirconium and its compounds are listed undersubstances that must not form part of the composition of cosmetic products, with the exception of complexes in Annex III,Part I. These complexes are aluminum zirconium chloride hydroxide complexes and the aluminum zirconium chloridehydroxide glycine products used in antiperspirants; and the zirconium lakes, salts, and pigments of coloring agents listed inreference 3 in Annex IV, Part I (Cosmetics Directive of theEuropean Union 1995).
Aluminum Silicate, anhydrous, Calcium Silicate, Magnesium Aluminum Silicate, Magnesium Silicate, Bentonite, Hectorite, Kaolin, Montmorillonite, Pyrophyllite, and Zeolite arelisted in the Japanese Comprehensive Licensing Standards by
Category (CLS) (Rempe and Santucci 1998). Aluminum Silicate, anhydrous has no concentrations limits and is listed in all
categories except eyeliner preparations and lip preparations. Calcium Silicate, is listed in all categories. Magnesium Aluminum
Silicate, which is listed under Aluminum Magnesium Silicate,is listed in all categories. Magnesium Silicate is listed in all
categories. Hectorite is listed in all categories except eyeliner
preparations, lip preparations, and oral preparations. Montmorillonite is excluded from only eyeliner preparations. Pyrophyllite is listed in all groups except eyeliner, lip, oral, and bath
preparations. Bentonite, Kaolin, and Zeolite are listed in all
categories.
Information on use of ingredients in cosmetic formulations
is available from the Food and Drug Administration (FDA) as
part of a voluntary industry reporting program (FDA 1998).
These data are presented in the first two columns ofTable 6.
In addition, the Cosmetic, Toiletry, and Fragrance Association (CTFA) provides information from the industry directly
to CIR on the current concentration of use (CTFA 1999a). In
some cases a current concentration of use is provided even when
there is no current use reported to FDA. It is presumed that anindustry report of a current concentration of use means the ingredient is in use. These data are included in the third column ofTable 6.
In those cases where there is a use reported to FDA, butthere is no current concentration of use data available, the lastcolumn in Table 6 includes historical data from 1984 when FDA
collected information on concentration as part of the voluntary
reporting program described earlier (FDA 1984). If no historical
data are available, no concentration is listed.
Aluminum Silicate
Aluminum Silicate functions as an abrasive, anticaking agent,bulking agent, and opacifying agent in cosmetics (Wenninger
et al. 2000). In 1998 it was reported as an ingredient in 10 formulations in seven different categories (FDA 1998).

Distributed for Comment Only -- Do Not Cite or Quote

48

COSMETIC INGREDIENT REVIEWTABLE 6Frequency of use and concentration of use as a function of product category
Product category(Number of formulations
reported to FDA 1998)

Number of formulations
containing ingredient(FDA 1998)

Current concentrationof use (CTFA 1999a)(%)

Historical concentrationof use (FDA 1984)(%)

Mascara (167)
Blushers (all types) (238)
Dentifrices (38)
Shaving cream (139)
Cleansing (653)
Paste masks (mud packs) (255)
Skin fresheners (184)
Other skin preparations (692)1998 total uses of Aluminum Silicate

Aluminum Silicate
2
1
—
1
2
1
1
2
10

Bath oils, tablets, and salts (124)
Bubble baths (200)Other bath preparations (159)
Eye shadow (506)Powders (247)
Blushers (all types) (238)
Face powders (250)Foundations (287)
Lipstick (790)
Makeup bases (132)
Rouges (12)Other makeup preparations (135)
Other manicuring preparations (61)Skin cleansing preparations (653)
Men/s talcum (8)Calcium Silicate
12
2
2
11
35
17
40
5
3
1
1
1
1
1
—

—
—
—
1–8
2
5–8
0.3–10
2–8
0.5
0.5
—
—
—
8
8

0.1–5
0.1–25
0.1–25132
Magnesium Aluminum Silicate
1
20
4
1
2
33
—
—
16
1
1
1
3
—
3
3
1
130
3
60

—
—
1
1
—
0.4–5
0.2–0.5
0.5
1–5
—
—
—
—
2
1–2
—
—
0.4–5
—
1–2

—
0.1–25

1998 total for Calcium Silicate
Other bath preparations (159)
Eye makeup remover (84)
Eye shadow (506)
Eye lotion (18)
Eye makeup remover (84)
Mascara (167)
Eyeliner (514)
Eyebrow pencil (91)
Other eye makeup preparations (120)
Cologne and toilet waters (656)
Other fragrance preparations (148)Hair conditioners (636)Hair straighteners (63)Hair dyes and colors (1572)
Shampoos (noncoloring) (860)
Other hair preparations (276)Hair rinses (coloring) (33)Foundations (287)
Lipstick (790)
Makeup bases (132)

0.5
—
37
—
2
—
—
3

—
—
1–5
0.1–1

1–5
1–5
1–5

0.1–25

—
>0–1
0.1–1
0.1–1

—
—
0.1–1
(Continued on next page)Distributed for Comment Only -- Do Not Cite or Quote

49

SILICATESTABLE 6Frequency of use and concentration of use as a function of product category (Continued)
Product category(Number of formulations
reported to FDA 1998)

Number of formulations
containing ingredient(FDA 1998)

Current concentrationof use (CTFA 1999a)(%)

Makeup fixatives (11)Other makeup preparations (135)
Cuticle softeners (19)Nail creams and lotions (17)Dentifrices
Bath soaps and detergents (385)Deodorants (underarm) (250)
Other personal cleanliness products (291)Aftershave lotion (216)
Other shaving preparations (60)Skin cleansing preparations (653)
Face and neck skin care preparations (263)
Body and hand skin care preparations (796)Foot powders and sprays (35)
Moisturizers (769)Night creams, lotions, powders, and sprays (188)
Paste masks (mud packs) (255)
Other skin care preparations (692)Suntan gels, creams, and liquids (136)
Indoor tanning preparations (62)1998 total for Magnesium Aluminum Silicate

3
24
1
1
—
1
5
14
9
2
41
16
56
3
70
11
34
33
6
19
632
Attapulgite
5—510
Bentonite
—
6
1
1
1
3
5
3
1
1
2
6
1

2
0.8
—
—
0.7
0.5–1
0.5–1
2
—
—
0.1–5
0.6–3
0.3–5
—
0.3–4
0.3–2
3–5
0.1
2–5
0.5–2

6

2–5

2
1
44
1

3
—
12–80
—

Powders (fragrance) (247)
Body and hand skin care preparations (796)Paste masks (mud packs) (255)1998 total for Attapulgite
Bath, oils, tablets, and salts (124)Eyeliner (514)
Mascara (167)
Other eye makeup preparations (120)Hair conditioners (636)Hair straighteners (63)Foundations (287)
Makeup bases (132)
Cuticle softeners (19)Bath soaps and detergents (385)Other personal cleanliness products (291)
Skin cleansing preparations (653)
Face and neck skin care preparations(excluding shaving) (263)
Body and hand skin care preparations(excluding shaving) (796)Moisturizers (769)Night creams, lotions, powders, and sprays (188)
Paste masks (mud packs) (255)
Skin fresheners (184)

—
8
8

5
5
0.8
—
—
—
2–8
1
1
0.5
—
—
2–5

Historical concentrationof use (FDA 1984)
(%)

—
0.1–5

1−>50
0.1–5

—

—

—
—
0.1–1

0.1–10>0–10——(Continued on next page)Distributed for Comment Only -- Do Not Cite or Quote

50

COSMETIC INGREDIENT REVIEWTABLE 6Frequency of use and concentration of use as a function of product category (Continued)
Product category(Number of formulations
reported to FDA 1998)
Other skin preparations (692)Suntan gels, creams, and liquids (136)
Other suntan preparations (38)1998 total for Bentonite
Paste masks (mud packs) (255)
Other skin preparations (692)1998 total for Fuller’s Earth

Number of formulations Current concentration Historical concentration
containing ingredient of use (CTFA 1999a)of use (FDA 1984)(FDA 1998)
(%)
(%)
8
1
—
73
Fuller’s Earth2
1
3

Hectorite
Eyeliner (514)3
Mascara (167)1
Shampoos (noncoloring) (860)—Hair bleaches (113)5Foundations—
Other makeup preparations (135)1Basecoats and undercoats (manicuring) (48)1Nail polish and enamel (80)1Deodorants (underarm) (250)1Other personal cleanliness products (291)1Paste masks (mud packs) (255)2
Skin cleansing preparations (653)—
Body and hand creams, lotions, powders, and sprays (796)—
Other skin preparations (692)1Paste masks (mud packs) (255)—
Other suntan preparations (38)11998 total for Hectorite
18
Sodium Magnesium Silicate
Eyeliner—Eye shadow (506)11
Mascara (167)1Other eye makeup preparations (120)1
Powders (fragrance) (247)1
Tonics, dressings, and other hair-grooming aids (549)1Blushers (all types) (238)2Face powders (250)3Foundations (287)4Lipstick (790)1
Makeup bases (132)—
Other makeup preparations (135)1
Dentifrices (38)—Deodorants (underarm) (250)—Skin cleansing preparations (653)—
Face and neck skin care preparations
3(excluding shaving) (263)
Body and hand skin care preparations
2(excluding shaving) (796)Moisturizers (769)
1

—
—
1

—
—

—
—

—
25–50

—
0.7
1
—
15
—
—
—
0.7
—
0.4
100
8
—
8
—

—

0.08
0.08
0.4
—
—
—
—
0.4
0.4
3
0.1
—
0.3
0.5
0.5
0.8–5

—
1–5
—
—
—

—

—
—
—
—

—

0.1
1
(Continued on next page)Distributed for Comment Only -- Do Not Cite or Quote

51

SILICATESTABLE 6Frequency of use and concentration of use as a function of product category (Continued)
Product category(Number of formulations
reported to FDA 1998)

Number of formulations Current concentration Historical concentration
containing ingredient of use (CTFA 1999a)of use (FDA 1984)(FDA 1998)(%)(%)

Paste masks (mud packs) (255)
Skin fresheners (184)
Other skin preparations (692)1998 total for Sodium Magnesium Silicate

1
—
1
34

5
5
—

1–5

KaolinOther bath preparations (159)
Eyebrow pencil (91)
Eyeliner (514)
Eye shadow (506)
Mascara (167)
Other eye makeup preparations (120)
Powders (247)Hair conditioners (636)
Tonics, dressings, and other hair-grooming aids (549)
Other hair-coloring preparations (59)Blushers (all types) (238)
Face powders (250)Foundations (287)
Lipstick (790)
Makeup bases (132)
Rouges (12)Makeup fixatives (11)Paste masks (mud packs) (255)
Other makeup preparations (135)Bath soaps and detergents (385)Other manicuring preparations (61)Skin cleansing preparations (653)
Face and neck skin care preparations (263)
Moisturizers (769)
Skin fresheners (184)
Other skin care preparations (692)Suntan gels, creams, liquids (136)1998 total for Kaolin

1
5
9
171
31
15
40
5
—
1
72
58
45
6
24
2
3
—
20
1
—
—
—
—
—
—
—
509

Attapulgite
Attapulgite functions as an abrasive, bulking agent, opacifying agent, and viscosity-increasing agent (Wenninger et al.
2000). The FDA reported in 1998 Attapulgite being used in 10
formulations (FDA 1998).

Calcium Silicate
Calcium Silicate functions as an absorbent, bulking agent,
and an opacifying agent in cosmetic formulations (Wenninger
et al. 2000). The FDA reported 132 formulations containing
Calcium Silicate in 1998, of which 30% of the formulations
were face powders (FDA 1998).

Bentonite
Bentonite functions as an absorbent, bulking agent, emulsion
stabilizer, opacifying agent, suspending agent—nonsurfactant,and viscosity-increasing agent—aqueous in cosmetic formulations (Wenninger et al. 2000). In 1998, 94 formulations werereported (FDA 1998). Of the 94 formulations, 47% were reported within paste masks (mud packs) (FDA 1998).

1–10
15–17
25–48
3–29
8–18
20
5
4
15
5
14–20
30
6–36
12–30
7–25
—
—
12–84
10–24
3
53–54
0.01
3
25
2
3–100
25

>0–50
1–5

Fuller’s Earth
Fuller’s Earth functions as an absorbent, anticaking agent,bulking agent, and opacifying agent (Wenninger et al. 2000).
Fuller’s Earth was reported in three formulations in 1998 (FDA1998).

Distributed for Comment Only -- Do Not Cite or Quote

52

COSMETIC INGREDIENT REVIEWHectorite
Hectorite functions as an absorbent, bulking agent, opacifying agent, suspending agent—nonsurfactant, and viscosityincreasing agent—aqueous (Wenninger et al. 2000). In 1998,
Hectorite was reported in 18 formulations (FDA 1998). Rheox
Inc. (1999a) reported Hectorite as being used in antiperspirants,
suntan products, eye products, hair products, creams and lotions,lip products, facial masks, and nail products.
KaolinKaolin functions as an abrasive, absorbent, anticaking agent,bulking agent, and opacifying agent in cosmetic formulations(Wenninger et al. 2000). Of the 509 formulations reported by
FDA in 1998, 34% were eye shadows (FDA 1998).
Lithium Magnesium Silicate
Lithium Magnesium Silicate functions as a binder, bulking
agent, and viscosity-increasing agent—aqueous in cosmetic formulations (Wenninger et al. 2000). There were no current uses
reported to FDA.
Lithium Magnesium Sodium Silicate
Lithium Magnesium Sodium Silicate functions as a bulking agent and viscosity-increasing agent—aqueous (Wenninger
et al. 2000). There were no current uses reported to FDA.
Magnesium Aluminum Silicate
Magnesium Aluminum Silicate functions as an absorbent, anticaking agent, opacifying agent, and viscosity-increasing

agent—aqueous in cosmetics (Wenninger et al. 2000). It wasreported that Magnesium Aluminum Silicate was used in 629
formulations in 1998 (FDA 1998). Of those 629 formulations,
21% were used in foundations.
Magnesium Aluminum Silicate (VEEGUM) was reported by
Carlson (1977) to typically be used at a concentration of 1%
to 2%, consistent with the data in Table 6. Another source reported Magnesium Aluminum Silicate used at concentrationsof 10% to 50% for adsorbents, 0.5% to 2.5% for stabilizing
agents, 1% to 10% for suspending agents, 2% to 10% for tablet
and capsule disintegrants, 2% to 10% tablet binders, and 2% to
10% viscosity-increasing agents, again consistent with data in
Table 6 (Palmieri 1994).
Additional historical data on concentration of use of this ingredient are available from a Toilet Good Association survey.
Table 7 is a summary of that information (Toilet Goods Association 1969).
Magnesium Silicate
Magnesium Silicate functions as an absorbent, anticaking
agent, bulking agent, opacifying agent, and viscosity-increasing
agent—aqueous in cosmetic formulations (Wenninger et al.
2000). There were no current uses reported to FDA.
Magnesium Trisilicate
Magnesium Trisilicate functions as an abrasive, absorbent,
anticaking agent, bulking agent, opacifying agent, and viscosityincreasing agent—aqueous in cosmetics (Wenninger et al. 2000).

TABLE 7
Magnesium Aluminum Silicate in cosmetic preparations (Toilet Goods Association 1969).
Product category
Face cream/lotion (cleansing, hormone, night,
acne, astringent)
Hand cream/lotion
Body cream/lotion (moisturizer,
suntan preparations)
Makeup (lotion, cream, medicated,matte, highlight)
Rouge (cream, liquid, blusher, toner)
Face mask
Powder aerosol
Powder compact/pressed
Leg makeup
Deodorant/antiperspirant
Eye makeup (eyeshadow, mascara, eyeliner)
Depilatory
Shave preparations
ShampooCream sachet

Use in productConcentration(%)

Thickener, binder, emulsion stabilizer

2.1

Thickener, binder, emulsion stabilizer
Thickener, binder, emulsion stabilizer,
slip agent
Thickener, binder, emulsion stabilizer,
pigment suspender
Thickener, binder, pigment suspender
Thickener, binder
Anticaking
Oil absorption
Thickener
Thickener, emulsion stabilizer
Thickener, emulsion stabilizer, pigment suspender
Thickener
Thickener
Thickener
Thickener, emuslion stabilizer

1.3
1.6
1.8
1.8
8.9
8.0
1.0
3.9
1.8
2.0
2.0
0.5
3.5
0.8

Distributed for Comment Only -- Do Not Cite or Quote
SILICATES

Montmorillonite
Montmorillonite functions as an abrasive, absorbent, emulsion stabilizer, opacifying agent, and viscosity-increasing
agent—aqueous in cosmetics (Wenninger et al. 2000). There
were no current uses reported to FDA.
Pyrophyllite
Pyrophyllite functions as an absorbent, colorant, and opacifying agent (Wenninger et al. 2000). There were no current uses
reported to FDA.
Sodium Magnesium Silicate
Sodium Magnesium Silicate functions as binder and bulking
agent (Wenninger et al. 2000). In 1998, Sodium Magnesium
Silicate was reported in 34 formulations (FDA 1998).
ZeoliteZeolite functions as an absorbent and deodorant agent in cosmetic formulations (Wenninger et al. 2000). There were no current uses reported to FDA.
Zirconium Silicate
Zirconium Silicate functions as an abrasive and opacifying
agent in cosmetic formulations (Wenninger et al. 2000). There
were no current uses reported to FDA.
Noncosmetic
Aluminum Silicate
Aluminum Silicate is approved, under the heading of indirectfood additives, as a substance used as basic components of single
or repeated use of the food contact surfaces cellophane (21 Codeof Federal Regulations [CFR] 177.1200) and rubber (21 CFR
177.2600).
Attapulgite
Attapulgite is listed in the OTC Active Ingredient Status Report as proposed category I, as an antidiarrheal ingredient (FDA
1994). Attapulgite is listed by Gamble (1986) as being primarily
used in absorbents, pesticides, oil and petroleum treatment, andas a filler in many products.
Bentonite
Bentonite is considered by FDA to be generally recognized
as safe (GRAS) as a direct food additive (21 CFR 184.1155).
Bentonite is listed by Gamble (1986) as being used in foundrysand bonding, bleaching clay in oil refining and decolorizers, filtering agents, water impedance, animal feed, pharmaceuticals,
paint, plasticity increasers, and iron-ore pelletizing. Anothersource reported Bentonite as being used as an adsorbent, emulsion stabilizer, and suspending agent (Belmonte 1994). Bentonite is categorized by the National Formulary as a suspending
and/or viscosity-increasing agent (United States Pharmacopeial
Convention, Inc. 1994).

53

Calcium Silicate
Calcium Silicate is listed in the OTC Active Ingredient Status Report as an external analgesic and skin protectant (FDA
1994). The National Formulary category is as a glident and/or
anticaking agent (United States Pharmacopeial Convention, Inc.
1994).
The American Conference of Governmental Industrial Hygienists (ACGIH) TLV-TWA (threshold limit value–time weighted average) is 10 mg/m3 for inhalable dust (ACGIH 1997).
Hectorite
Hectorite has two listings of category IISE in the OTC Active
Ingredient Status Report (FDA 1994). It is listed as being used
as an external analgesic and skin protectant. Barr (1957) statedthat the Federal Drug Administration (sic) has given approval
for the use of Hectorite in internally and externally applied products, as well as dentifrices, cosmetics, and externally approved
pharmaceuticals.
KaolinAccording to FDA, Kaolin is considered GRAS as an indirect food additive (21 CFR 186.1256). Kaolin is listed as being
used in antacids, anorectals (external and interrectal), antidiarrheals, skin protectants, and digestive aids (colloidal Kaolin)in the OTC Active Ingredient Status Report. The final rulings
are as follows: antacids: category IIE; anorectals (both): category I; and digestive aid: category IISE. Proposed rulings are
as follows: antidiarrheal: category IIIE; skin protectant diaper
rash: category I; skin protectant poison ivy: category I; and skinprotectant: category I. Category III is designated as the conditions for which the available data are insufficient to permit finalclassification at this time.
Gamble (1986) reports Kaolin’s main use in the paper industry to fill and coat the surface of paper. Kaolin is also reported being used as a filler in rubber, paint extender, filler
in plastics, ceramics manufacture, ink, adhesives, insecticides,
medicines, food additives, bleaching, adsorbents, cement, fertilizers, crayons, pencils, detergents, porcelain enamels, paste,foundries, linoleum, floor tiles, and textiles.
The National Formulary classifies Kaolin as a tablet and/or
capsule diluent (United States Pharmacopeial Convention, Inc.
1994).
The Food Chemicals Codex specifies limits of impurities
for clay (Kaolin) as: acid-soluble substances <2%; Arsenic (asAs) <3 ppm; Heavy Metals (as Pb) <40 ppm; Lead <10 ppm(National Academy of Science 1996).
Magnesium Aluminum Silicate
Magnesium Aluminum Silicate (MAS) is listed as being usedin acne treatments and in antacids in the OTC Active Ingredient
Status Report (FDA 1994). As an antacid, MAS is a category I
listing, meaning it is generally recognized as safe and effective
and is not misbranded. However, MAS is a category IISE listing
as used for acne. MAS was listed as category IISE due to safety
and/or effectiveness.

Distributed for Comment Only -- Do Not Cite or Quote

54

COSMETIC INGREDIENT REVIEWOther uses for Magnesium Aluminum Silicate have been reported as: adsorbent, suspending agents, tablet and capsule disintegrant, tablet binder, and viscosity-increasing agent (Palmieri1994).
The National Formulary classifies Magnesium Aluminum
Silicate as a suspending and/or viscosity-increasing agent(United States Pharmacopeial Convention, Inc. 1994).
VEEGUM, a tradename for Magnesium Aluminum Silicate,has been designated by the FDA as a raw material with thefollowing number: FD-CRMCS no. R0010045 and has an individual Chemical Abstract Registry (CAS) number 12199-37-0.
Magnesium Silicate
Magnesium Silicate is classified as a glidant or anticaking
agent by the National Formulary (United States Pharmacopeial
Convention, Inc. 1994).
Magnesium Trisilicate
Magnesium Trisilicate is listed in the OTC Active Ingredient Status Report as being used as antacids, digestive aids,
and overindulgence remedy (FDA 1994). In antacids, FDA has
listed Magnesium Trisilicate as category I (generally recognized
as safe and effective). FDA concluded that Magnesium Trisilicate use in digestive aids is category IISE (not generally recognized as safe and effective). FDA has proposed that Magnesium
Trisilicate use in overindulgence remedies is category I.
Pyrophyllite
Pyrophyllite is listed under Code of Federal Regulations (21CFR 73.1400) as a naturally occurring color additive and must
conform to the following specifications: lead (as Pb) not morethan 20 ppm; and arsenic (as As) not more than 3 ppm. Also
Pyrophyllite may be used safely for coloring externally applied
cosmetics, in amounts consistent with good manufacturing practice (21 CFR 73.2400).
Pyrophyllite is listed by Gamble (1986) as being used in refractories, rubber, ceramics, insecticides, plastics, paint, roofing,bleaching powder, textiles, cordage, and wall board.
ZeoliteZeolites are reported by Gamble (1986) as being used in
CO2 recovery from natural gas, aromatic separates dimension
stones, filler in paper, isolation of radioactive wastes, water aeration, dietary supplements for animals, neutralization of acidic
soils, carriers for pesticides and fungicides, sorbents for oil
spills, polishing agent in toothpastes, and petroleum solvents.
International Agency for Research on Cancer (IARC) (1997)
lists the three main uses of synthetic Zeolite as: detergents, catalysts, and adsorbents or desiccants.
Zirconium Silicate
Zirconium Silicate is reported by Kleber and Putt (1986) as
being used in chewing gum and in a dental prophylaxis paste.

GENERAL BIOLOGY
Adsorption
The large volume of general data available on the adsorption of various chemicals, cells, etc., to these silicate clays ispresented in Table 8. In addition, to this general information,
specific reactions are described using specific silicate clays—these data are described below.
Hectorite
Bujdak and Rode (1996) reported that Hectorite-catalyzed
glycine and diglycine oligomerizations were performed as
drying/wetting cycles. Approximately 7% of glycine was converted to diglycine and diketopiperazine on Hectorite after
7 days. It may be noted that the Hectorite sample was altered bysubstituting Li(I) for Mg(II), which caused a greater effect onoligomerizations.
Porter et al. (1998) reported condensation reactions of theamino acid glycine on the surface of Cu(II)-exchanged Hectorite. Polymerization of gylcine oligomers was seen primarily
at the edges or topmost layer. These reactions were facilitatedby the availability of intergallery metal cations at the step edges
or pores in the surface region.
KaolinAdenosine monophosphate molecules were adsorbed onto
Kaolinite, modified with Mg2+ and irradiated with ultraviolet(UV) light. These synthesis products were tested for their bondtypes by enzymatic hydrolysis and analyzed by ion-exchange
chromatography. Considerable portions of the products were
phosphodiesterase hydrolyzed, which implies a 30 –50 , 20 –50 , orboth, nature of the bonds (Strigunkova, Lavrentiev, andOstroshchenko 1986).
Montmorillonite
Dougherty et al. (1985) incubated Montmorillonite saturated
with magnesium chloride (10 mg) with 5 × 106 human neutrophils. Effects were determined by phase contrast microscopic
examination and by the measurement of lactate dehydrogenase.
Both untreated and clay treated with human albumin were used tostimulate neutrophil chemiluminescence. Montmorillonite wasalso incubated with human erythrocytes and the free hemoglobin
was measured at 430 nm and the effect of clay on zymosanactivated serum was also investigated. Rapid neutrophil lysis
was observed in cells exposed to untreated clay. After lysis,
lactate dehydrogenase rapidly adsorbed to the surface of theclay. Clay pretreatment with human albumin blocked the enzyme surface adsorption and cell lysis. Neutrophil chemiluminescence was stimulated by untreated clay but not by clay
pretreated with 5% albumin. Clay lysis of erythrocytes was incomplete as compared to neutrophil lysis. Zymosan-activatedserum samples exposed to clay; complement activity as measured by neutrophil chemotaxis was suppressed in a dosedependent manner.

Distributed for Comment Only -- Do Not Cite or Quote

55

SILICATESTABLE 8Adsorption of various chemicals, cells, etc., to Silicate clays
Compound adsorbed
Dicumarol

Streptomycin sulphate andneomycin sulphate

Bromohexine HCL

Tetracycline

Trimethoprim

Aminosidine sulphate,chloramphenicol,
erythromycin, neomysin
B sulphate, novobiocinsulphate, penicillin V,
streptomycin sulphate,
and tetracyclinehydrochloride
Ampicillin and amoxycillin

Strychnine, quinine, andatropine

Experimental design

Results

Magnesium Aluminum Silicate
The drug dicumarol was given to Significantly lower plasma levels anddogs with 50% colloidal
delayed appearance of dicumarol
Magnesium Aluminum
resulted from administration with 50%
Silicate (MAS); the plasma
MAS; drug concentration at peak level
level of dicumarol in dogs was
was 16.7% (25.8% in controls) andmeasured
peak plasma levels were seen at
12–24 h (8–12 h in controls)
Adsorption studies were carried
MAS had the greatest affinity forout in vitro in McIlvaine’s
streptomycin sulphate in water
Buffer and water(adsorption coefficient of 111 · 10−3 forwater and 33 · 10−3 ) whereas theadsorption coefficient for MAS in waterto neomycin sulphate was 34 · 10−3
Bromohexine remaining in the tablets
MAS was mixed withincreased with increasing
bromohexine HCL to makeconcentrations of MAS, indicating thattablets and were stored in
MAS prevented the adsorption ofpolyethylene film for various
bromohexine to polyethylene film; notimes; the amount of
bromohexine remaining in the
bromohexine degradation was reported
tablet was determined
In vitro and in vivo adsorption of The maximum serum concentration oftetracycline by VEEGUM wastetracycline was decreased by 21%; thestudiedmaximum adsorption in vitro occurredat pH 1.2, where the % adsorbed
ranged from 91.5% to 97.2%
The mean decrease in the maximum
The concentration oftrimethoprim in the blood was
blood concentration of trimethoprim
determined at 0, 15, and 30
was 49.94%
min and 1, 2, 4, and 6 hEach antibiotic was added to 250 Magnesium Trisilicate reduced themg of magnesium trisilicate;
activity of all antibiotics except
the antibiotic activity waschloramphenicoldetermined by cup-plate
method using Staphylococcus
aureusIn vitro adsorption anddesorption studies werecarried out at different pHs

Hydrated silica gel formed fromdecomposition of the antacid at pH 2.1
and Magnesium Trisilicate had no
adsorptive effect on either antibiotic

Reference
Akers, Lach,and Fischer
1973

Ghazy, Kassem,and Shalaby
1984

Kukita et al.
1992

Healy et al. 1997

Babhair andTariq 1983

El-Nakeeb andYoussef 1968

Khali, Mortada,and
El- Khawas
1984aAttapulgite
Adsorption isotherms for each of Attapulgite adsorbed strychnine better
Evcim and Barrthe drugs and the clay wasthan atropine than quinine; an increase
1955
determined using
in the hydrogen ion concentration was
spectrophotometric orfound to have a slight decreasing effectcolorimetric methods
on the adsorptive ability for strychnine(Continued on next page)Distributed for Comment Only -- Do Not Cite or Quote

56

COSMETIC INGREDIENT REVIEWTABLE 8Adsorption of various chemicals, cells, etc., to Silicate clays (Continued)
Compound adsorbed
Strychnine and atropine

Agrobacterium radiobacter

Vibrio cholerae andEscherichia coli
enterotoxins

Ampicillin and amoxycillin

Escherichia coli, Serratia
marcescens, and Bacillus
speciesEscherichia coli 0111
endotoxins (ETU 144,
150, and 153)

Zearalenone and nivalenol

Aflatoxins B1 , B2 , G1 , G2 ,M1Strychnine and atropine

Experimental design

Results

Reference

Activated attapulgite was added
to both compounds andadsorption isotherms were
calculated
The measurement of O2 uptake
by calculating the respiration
quotients (QO2 ) was
performed on all species ofbacteria in the presence of 2%
Kaolin with either adjusted(7.0) or unadjusted pHs
The toxins and Attapulgite were
injected into the intestinal
loop of rabbits

Both compounds were adsorbed by
Attapulgite; optimum adsorbent
properties were calculated at pH 6.8
and 7.2
Attapulgite contained excess basic
cations, which accounted for the initialhigh pH and the reduction on
respiration elicited by the addition of
buffer

Barr and Arnista
1957

Attapulgite prevented the toxic effects
caused by enterotoxins in the intestinal
loop by adsorption; Attapulgite was
effective when injected simultaneouslywith the toxin and before the toxin is
injected
Both drugs were adsorbed at pH 2.1;
In vitro adsorption anddesorption studies weredesorption experiments at pH values of
2.0 and 6.5 showed only partial releasecarried out at different pHsof the adsorbed antibiotics
Bentonite
Each organism was cultivated in All organisms were absorbed bybroth portions with 3% andBentonite at each concentration;
10% Bentonite
Bacillus species was almost completely
absorbed at each concentration
In vitro and in vivo endotoxin
In vitro, Bentonite was an effective
binding was studied
endotoxin binder and binding was pH
dependent (lower pHs yielded better
results); 75 mg completely eliminatedendotoxemia. At pH 3.0, the ED50 was
20 mg
20 or 50 g/kg of Bentonite wasBentonite was unsuccessful at
added to the feed of pigs
overcoming the estrogenic or depressedcontaminated withperformance effects caused by thezearalenone and nivalenol andmycotoxins
was ingested for 29 days
Various methods
2% Bentonite adsorbed 400 µg of B1 ; 2%adsorbed 89% of M1 ; 2.5% adsorbed
5 ppm of B1 and G1 and 0.5 to 5 ppm
of B2 and G2 ; 10% adsorbed 70% B1

Kaolin was added to bothcompounds and adsorption
isotherms were calculated

KaolinBoth compounds were adsorbed by
KaolinStotzky 1966

Drucker et al.
1977

Khali, Mortada,and ElKhawas
1984aNovakova 1977

Ditter,Urbaschek,
and Urbascek
1985

Williams,
Blaney, andPeters 1994

Ramos, FinkGremmels,
andHernandez
1996
Barr and Arnista
1957(Continued on next page)Distributed for Comment Only -- Do Not Cite or Quote

57

SILICATESTABLE 8Adsorption of various chemicals, cells, etc., to Silicate clays (Continued)
Compound adsorbedExperimental design

Results

Reference

Aminosidine sulphate,chloramphenicol,
erythromycin, neomysin
B sulphate, novobiocinsulphate, penicillin V,
streptomycin sulphate,
and tetracyclinehydrochloride
Agrobacterium radiobacter

Each antibiotic was added to
250 mg of Kaolin; theantibiotic activity wasdetermined by cup-plate
method using Staphylococcus
aureusKaolin adsorbed significant amounts ofaminosidine, neomysin, streptomycin,
and tetracycline; Kaolin had no effecton antibiotic activity

El-Nakeeb andYoussef 1968

The measurement of O2 uptake
by calculating the respiration
quotients (Q O2 ) was
performed on all species ofbacteria in the presence of 2%
Kaolin with either adjusted(7.0) or unadjusted pHs
The measurement of O2 uptake
by calculating the respiration
quotients (Q O2 ) was
performed on all species ofbacteria in the presence of 2%
Kaolin with either adjusted(7.0) or unadjusted pHs

Kaolin did not maintain the pH therefore
the bacteria could not maintainrespiration even with an optimal pH for
growthStotzky 1966

Kaolin in unadjusted pH systems reduced
respiration of the bacteria below that ofcultures without clay; but in adjusted
systems some stimulation of
respiration with the addition of Kaolin
was apparent

Stotzky andRem 1966

Fungal mycelium and Kaolinite
were cultured together and theO2 uptake and pH wererecorded
2 g of Kaolin was added to
100 ml of a crystal violet
solution
Suspension of the organism,
Kaolinite, and NaCl werestudied

Kaolinite concentrations <4% generally
did not effect respiration; respiration
was only markedly inhibited atconcentrations >40%
Adsorption was examined over a pH
range of 2.5–9.5; adsorption increased
with increasing pH
Increasing electrolyte concentration was
accompanied by increased edge-to-face
Kaolinite flocculation andorganism-Kaolin aggregatesE. coli was absorbed by Kaolin at bothconcentrations; the greatest adsorption
occurred at 10% Kaolin at all phases ofbacterial growth
The maximum adsorption occurred at
pHs below 4.1; minimal values
occurred at pH 4.1, 7.4, and 8

Stozky and Rem
1967

Bacillus subtilis, Bacillus
megaterium, Aerobacteraerogenes, Escherichia
intermedia, Pseudomonas
aeruginosa and
P. aeroginosa C-II,
Flavobacterium species,
Proteus vulgaris
Mycelial homogenates of 27
species of fungi

Crystal violet

Staphylococcus aureus

Escherichia coli

E. coli was cultivated in broth
portions with 3% and 10%
Kaolinite

125

The in vitro adsorption of thetoxin by Kaolin wasinvestigated over a range ofpHs
In vitro (pH 7.4) and in vivo
(rats) adsorption studies werecarried out

I-labeled Pseudomonas
aeruginosa toxin

Acetohexamide, tolazamide,
and tolbutamide

Armstrong and
Clarke 1971
Steel andAnderson
1972
Novakova 1977

Said, Shibal,
and Abdullah
1980

All 3 drugs bound and acetohexamide had Said andthe greatest binding; the hypoglycemic
Al-Shora
activity of the 3 drugs were suppressed1980
and blood glucose concentrations wereincreased; desorption of the drugs from
Kaolin ranged from 1.8% to 24.5%(Continued on next page)Distributed for Comment Only -- Do Not Cite or Quote

58

COSMETIC INGREDIENT REVIEWTABLE 8Adsorption of various chemicals, cells, etc., to Silicate clays (Continued)
Compound adsorbed
Coliphages T1 and T7 ofEscherichia coli

Trimethoprim

Experimental design

Results

Reference

1 ml suspensions of thecoliphages were added tovarious concentrations of
KaolinThe concentration oftrimethoprim in the blood wasdetermined at 0, 15, and30 min and 1, 2, 4, and 6 h in
the presence of Kaolin-Pectin
A Kaolinite solution with added
copper ions was added tosurfactants and the metal ion
uptake was recorded

Adsorption of both coliphages by Kaolin
were approximately the same 99%

Schiffenbauer
and Stotzky
1982

The mean decrease in the maximum
blood concentration of trimethoprim
was 29.42%

Babhair andTariq 1983

Cationic surfactant result: the equilibrium
between the metal ions and the organic
cations was not effected

Beveridge andPickering
1983

Cationic surfactants:
distearyl dimethyl
ammonium chloride(74%); lauryl
dimethylbenzyl
ammonium chloride(50%)
Anionic surfactants: sodium
alkylbenzene aulphonate(80%); Monoethanolaminelauryl sulphate (34%);lauryl alcohol
polyethylene condensate(28%)
Nonionic surfactants:
alcohol ethoylates;
tridecaml ethoxylate(90%); cetystearyl
alcohol ethoxylates;
stearic acid ethoxylate;cocnut monoethanolamide
ethoxylate; octadecylamine
ethoxylate; castor oil
ethoxylate; nonyl phenol
ethoxylates; dinonyl
pheno ethoxylate;polypropylene glycol
ethoxylates
Escherichia coli 0111
In vitro and in vivo endotoxin
endotoxins (ETU 144,
binding to Kaolin
150, and 153)

Reovirus type 3

Ampicillin and amoxycillin

Chymotrypsin, ovalbumin, andlysozyme were added to
Kaolinite and reovirus type 3
4 g of Kaolin was ingested and2 h later, 500 mg of the drugs
were administered. This
protocol was repeated 2 h laterand urine (human) samples
were collected

Anionic surfactants: increased metal
uptake by the clay was observed

Nonionic surfactants: many surfactants
had no effect and some caused
enhanced loss of the metal ions fromsolution

In vitro Kaolin was an effective endotoxin
binder and binding was pH dependent(lower pHs yielded better results); 300
mg of Kaolin eliminated endotoxemia,
at pH 7.4, the ED50 was 900 mg
Chymotrypsin and ovalbumin reduced theadsorption of reovirus but lysozyme
did not
All volunteers showed reduced drug
bioavailability following treatment;
after 8 h, the reduced bioavailability for
ampicillin ranged from 51.2 to 76.3
and 63.6 to 80.6 for amoxycillin

Ditter,Urbaschek,
and Urbascek
1983
Lipson andStotzky 1984
Khali, Mortada,
and
El-Khawas
1984b(Continued on next page)Distributed for Comment Only -- Do Not Cite or Quote

59

SILICATESTABLE 8Adsorption of various chemicals, cells, etc., to Silicate clays (Continued)
Compound adsorbedExperimental design

Ampicillin and amoxycillin

In vitro adsorption anddesorption studies to Kaolin(light, natural, and fine) werecarried out at different pHs

Reovirus type 3 andcoliphage T1

LT toxins of Vibrio choleraeand Escherichia coli, theST toxin of ETEC, andthe verotoxin of EHEC

Agrobacterium radiobacter

Bacillus subtilis, Bacillus
megaterium, Aerobacteraerogenes, Escherichia
intermedia, Pseudomonas
aeruginosa and P.
aeroginosa C-II,
Flavobacterium species,
Proteus vulgaris
Mycelial homogenates of
27 species of fungi

Cationic drugs:
chlorpheniramine
maleate, amphetamine
sulfate, andpropoxyphenehydrochloride;
Anionic drugs: not specified
Nonionic drugs: xanthines,
theophylline, and caffeine

Results

Reference

The 3 types of Kaolin adsorbed only
ampicillin and adsorption decreased as
the pH increased; only partial releaseof the antibiotics was seen at pH 2.0
and 6.5
Competitive adsorption studies
Reovirus type 3 and coliphage T1 did not
were carried out with Kaolin
share common adsorption sites onin estuarine water and distilled
Kaolin and the coliphage did not
water
interfere with the reovirus adsorption
in estuarine water; the reovirus had noapparent effect on the adsorption of thephage in estuarine water
Not specified
Kaolin inactivated the LT toxin andadsorption was a result of hydrogenbonding; it was ineffective against theverotoxin when the pH was alkaline;
Kaolin was only slightly effective
against the ST toxin
Montmorillonite
Montmorillonite spurred bacterial
The measurement of O2 uptake
respiration by maintaining the initial
by calculating the respiration
pH; when the pH was adjusted to 7.0
quotients (Q O2 ) was
performed on all species of
respiration was its highest and similarbacteria in the presence of 2%
to the buffered systems
Kaolin with either adjusted(7.0) or unadjusted pHs
Montmorillonite increased the respiration
The measurement of O2 uptakeof all species regardless of pH andby calculating the respiration
characteristics of the bacteria primarily
quotients (Q O2 ) was
performed on all species ofby maintaining the pH of the systems
bacteria in the presence of 2%favorable for growth
Kaolin with either adjusted(7.0) or unadjusted pHs
Fungal mycelium andMontmorillonite were
cultured together and the O2
uptake and pH were recorded
Dissolution and dialysis werecarried out in vitro

Montmorillonite concentrations <4%generally did not effect respiration;
respiration was markedly inhibited atconcentrations of 4% and above
All the cationic drugs and certain
nonionic drugs bound tenaciously; theanionic drugs and nonionic drugs thatexist as nonionics bound very weakly
and rapidly pass into solution

Khali, Mortada,
and
El-Khawas
1984aLipson andStotzky 1985

Brouillard andRateau 1989

Stotzky 1966

Stotzky andRem 1966

Stozky and Rem
1967

McGinity andLach 1976(Continued on next page)Distributed for Comment Only -- Do Not Cite or Quote

60

COSMETIC INGREDIENT REVIEWTABLE 8Adsorption of various chemicals, cells, etc., to Silicate clays (Continued)
Compound adsorbedExperimental design

Carbon tetrachloride, ethylene
dibromide, trichlorethylene

10–1000 ppb/water of thethree compounds were
exposed toaluminum-saturated
Montmorillonite andcalcium-saturated
Montmorillonite

Coliphages T1 and T7 ofEscherichia coli

1 ml suspensions of thecoliphages were added tovarious concentrations ofMontmorillonite
A Montmorillonite solution
with added copper ions
was added to surfactants
and the metal ion uptake
was recorded

Cationic surfactants: distearyl
dimethyl ammonium chloride(74%); lauryl dimethylbenzyl
ammonium chloride (50%)
Anionic surfactants: sodium
alkylbenzene aulphonate (80%);
monoethanolamine laurylsulphate (34%); lauryl alcohol
polyethylene condensate (28%);
Nonionic surfactants: alcohol
ethoylates; tridecaml ethoxylate(90%); cetystearyl alcohol
ethoxylates; stearic acidethoxylate; coconutmonoethanolamide ethoxylate;
octadecylamine ethoxylate;castor oil ethoxylate; nonyl
phenol ethoxylates; dinonyl
pheno ethoxylate; polypropylene
glycol ethoxylates
Reovirus type 3

Poliovirus-1 (Lsc 2ab strain)

Reovirus type 3 and coliphage T1

Results

Reference

Aluminum-saturated
Montmorillonite absorbed 17%of trichloroethylene and 6% of
the other cmpds;
calcium-saturated
Montmorillonite did not absorb
carbon tetrachloride ortrichloroethylene
Adsorption of T1 coliphages byMontmorillonite was 84% andT7 was 96%

Rogers and
MacFarlane
1981

Cationic surfactant result: metal ion
uptake was reduced bycompeting surface sites

Beveridge andPickering
1983

Schiffenbauer
and Stotzky
1982

Anionic surfactants: increased
metal uptake by the clay wasobserved

Nonionic surfactants: surfactants
reduced the amount of metal ion
adsorbed by the clay

Chymotrypsin, ovalbumin,and lyso-zyme were added
to Montmorillonite andreovirus type 3
500, 15, 3 mg/L of SodiumMontmorillonite and thevirus were suspended inseawater and theadsorption, desorption, andvirus survival were studied
Competitive adsorption
studies were carried out
with Montmorillonite inestuarine water anddistilled water

Chymotrypsin, ovalbumin, andlysozyme reduced the adsorptionof reovirus

Lipson andStotzky 1984

99.9% of the virus was absorbed in
Gantzer,less than 30 min; 500 mg/L of
Quignon, andNa-Montmorillonite significantly
Schwartzbrod
increased the survival duration of
1994
of the virus and desorption tests
showed elution of 76%
Reovirus type 3 and coliphage T1
Lipson anddid not share common adsorption
Stotzky 1985
sites on Kaolin and the coliphage
did not interfere with the reovirus
adsorption in estuarine water or
distilled water; the reovirus
suppressed the adsorption of thecoliphage in estuarine water(Continued on next page)Distributed for Comment Only -- Do Not Cite or Quote

61

SILICATESTABLE 8Adsorption of various chemicals, cells, etc., to Silicate clays (Continued)
Compound adsorbed
Agrobacterium radiobacter

Zearalenone

Aflatoxin B1

Experimental design

Results

Pyrophyllite
Pyrophyllite did not maintain a favorable
The measurement of O2 uptake
pH for sustained respiration in either
by calculating the respirationbuffered or nonbuffered systems
quotients (Q O2 ) was
performed on all species ofbacteria in the presence of 2%
Kaolin with either adjusted(7.0) or unadjusted pHs
Zeolite5% of a synthetic
The anion-exchange zeolite wasanion-exchange zeolite and acompletely effective and thecation-exchange zeolite andcation-exchange zeolite was not
250 µg/g of zearalenone wereadded to the feed of rats
The average aflatoxin retention rate was
Two samples of natural Zeolites
605; effectiveness was lower in media
in different liquids were
containing nitrogen compounds
incubated with B1

Bujdak and Rode (1996) reported peptide formation on thesurface of three Montmorillonite samples. The Montmorillonitecatalyzed reaction produced diglycine and diketopiperazine
from glycine.
Ferris et al. (1996) studied the catalytic properties of Na+ Montmorillonite by adding daily ImpA to a decanucleotide([32 P]-dA(pdA)8 pA, where Im = imidazole; pA = adenosine-50 phosphate; pdA = 30 -deoxyadenosine-50 -phosphate; 32 P =radioactively labeled phosphate group). Polyadenylates wereformed after two additions of ImpA, with the main products
being monomers ranging from 11 to 14. Polynucleotides, withmore than 50 monomers, were formed after 14 additions. The
principle oligomeric products contained 20 to 40 monomers.
Ertem and Ferris (1998) reported Montmorillonite-catalyzed
ImpA and ImpA-A50 reactions. Oligomer yields decreased significantly when the addition of alkylammonium or aluminum
poly oxo cations blocked the interlayer surfaces of the Montmorillonite particles.
Absorption, Distribution, Metabolism, and Excretion
Magnesium Trisilicate
Page, Heffner, and Frey (1941) measured the urinary excretion of silica in five men given 5 g of synthetic Magnesium
Trisilicate orally for 4 consecutive days. Urine samples werecollected for 24 h on the second day after the end of administration and analyzed for silica content. The mean 24-h excretionof all subjects was 16.2 mg of SiO2 . On the second, third, andfourth days after administration, the mean excretion rose to 172,
178, and 162 mg SiO2 . A total of 20 mg of Magnesium Trisilicate was taken and contained 9.2 g of SiO2 . An approximationof 5.2% SiO2 excretion was estimated.

Reference
Stotzky 1966

Smith 1980

Dvora’k 1989

Benke and Osborn (1979) conducted a study in which groupsof four to six male Sprague-Dawley Cox rats were fasted for 17
to 18 h and then were administered Magnesium Trisilicate orally
in doses of 40, 200, or 1000 mg/kg of their body weight. Control
animals received 10 ml of quartz-distilled water. All suspensions
contained <0.5 ppm of silicon and aluminum. Urine samples
were collected over an 8-h period, and the remaining urine in
the bladder was collected afterwards. The concentrations of silicon was measured by induction-coupled radiofrequency (RF)plasma optical emission spectrometry. Silicon excretion was
most rapid in the first 24 h after dosing. The control values weresubtracted from the final values and the following number resulted. The urinary silicon excretion at 40, 200, and 1000 mg/kg
Magnesium Trisilicate was 16.8%, 5.1%, and 1.5%, respectively.
Dobbie and Smith (1982) reported a 24-h urinary excretion
study in which Si was determined by atomic absorption spectroscopy in one male and one female participant. A normal dietwas given to the participants and four urine collections were
made. A single dose of Magnesium Trisilicate was ingested at
the beginning of the second 24-h collection. Magnesium Trisilicate doses given were as follows: 2, 5, and 10 g to the malesubject and 2.5, 5, and 7.5, and 10 g in the female subject. The
amount of Si excreted at the 5-g dose was greater than any otherdose in the male subject and was greater than the 2.5- and 7.5-g
doses in the female subject. The value of Si excretion for the maleand female subjects were 3.63 and 3.31 mmol/day, respectively.
Maximum excretion occurred in the first 24 h after ingestion.
The oral bioavailability of silicon and aluminum in Magnesium Trisilicate was studied by Cefali et al. (1995). Twelve
female beagle dogs were administered a single 20-mg/kg doseof Magnesium Trisilicate and their blood was sampled at 0,0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 h after dosing. The plasma

Distributed for Comment Only -- Do Not Cite or Quote

62

COSMETIC INGREDIENT REVIEW

samples were assayed for silicon and aluminum by graphite furnace atomic adsorption. No dogs displayed emesis, but four had
soft stool. The area under the curve (AUC, mg · h/L), concentration maximum (Cmax , mg/L), and time maximum (Tmax , h) for
silicon absorption was 8.8, 0.75, and 6.9, respectively. The AUC(mg · h/L), Cmax (mg/L), and Tmax (h) for aluminum absorption
was 315, 24, and 5.7, respectively. There was no statistically significant absorption of aluminum from the aluminum containing
compounds.
Montmorillonite
Retention of monodisperse and polydisperse Montmorillonite
particles inhaled by dogs, rats, and mice was studied by Snipes,
Boecker, and McClellan (1983a). Cations normally present inMontmorillonite were exchanged with 134 Cs. Polydisperse andmonodisperse 134 Cs-labeled Montmorillonite suspensions wereadministered to groups of 40 rats and mice and to 120 beagle dogs by a multiport nose-only inhalation exposure system.
Aerosol concentrations ranged from 10−3 to 10−1 mg of fused
Montmorillonite per liter of air. Equal numbers of male andfemale rats and mice and 74 male and 46 female dogs were utilized. Exposure times for rats and mice ranged from 25 to 45
min and for dogs 15 to 50 min. All animals were whole-bodycounted for the labeled particles. Rats and mice were counted
on exposure days 2, 4, 8, 16, 32, 64, 128, 256, 365, 512, 730,
and 850 and the dogs were also counted on the same schedule,
but also at 4, 5, 7, and 9 years after inhalation exposure. Excreta
collections were made for animals from each exposure group.
Five rats and five mice from each group were killed 4 h after
exposure. The remaining rats and mice were killed at various
times after exposure. Two dogs were scheduled for termination
at times ranging from 4 h to 9 years. All animals were necropsiedand tissues from lungs, lung-associated lymph nodes (LALNs),
gastrointestinal tract, spleen, kidneys, abdominal lymph nodes,
blood, skeleton, muscle, and skin were prepared for analysisof 134 Cs exposure. Results of the counts were converted into
disintegrations per minute.
The mass of material deposited into the lungs of rats and micewas ∼0.01 to 0.1 mg and for dogs was ∼1 to 10 mg. The massof Montmorillonite for all three species was <0.1 mg per gramof lung. Clearance of the initial 134 Cs occurred by dissolution
and mechanical clearance. Mechanical clearance from the nasopharynx was rapid, and the clearance rate was decreased toa negligible value for all three species within a few days. Most
initial deposit cleared via the gastrointestinal tract. Long-term
mechanical clearance from the pulmonary region occurred at aconstant rate for all species. Solubilization was the primary factor in long-term lung clearance for most particles inhaled by dogs
and mechanical clearance was dominant in rats and mice. Mostof the long-term clearance of deposited particles went to LALNs
in dogs and occurred at a slower rate as compared to rats andmice. Rats and mice had a rapid clearance from the pulmonary
region, where most of the mechanical clearance occurred via
the gastrointestinal tract. Long-term clearance of the particles

in dogs occurred at 3500-day half-time in the lymph nodes and
6900-day half-time clearance in the gastrointestinal tract. The
transport rate of the particles in the dog was 0.0002 day−1 ofthe lung burden. The long-term biological clearance half-term
day was 690 days for rats and 490 days for mice. The lymph
node accumulation process was modeled by a short-term process that became negligible after a few days (Snipes, Boecker,
and McClellan 1983a).
Snipes, Muggenburg, and Bice (1983b) instilled radio-labeled(134 Cs) fused Montmorillonite particles into specific lung lobes
or injected intraperitoneally into 32 beagle dogs. Necropsy was
performed at 34, 182, and 365 days later. Specific sites of instillation included right apical lobe, right cardiac lobe, right diaphragmatic lobe, right intermediate lobe, left apical lobe, left
diaphragmatic lobe, and intraperitoneal. Initial burdens in theperitoneal cavity or the lungs ranged from 0.50 to 14 µCi of134
Cs for 29 dogs and from 42 to 64 µCi of 134 Cs for lung burdens for the other three dogs. Effective translocation half-time oflung instillations was 390 days. The accumulation rate of 134 Cslabeled particles in the lymph nodes was 0.03% per day. Individual lung lobes cleared particles to one or two lymph nodes, andspecific lymph nodes accumulated particles from one to threelung lobes. Lymph nodes that collected particles from the lungincluded the left mediastinal node, left tracheobronchial lymph
node (TBLN), right TBLN, left middle TBLN, and right middle
TBLN. The destination for translocated particles were primarily
the nodes proximate to the tracheal bifurcation. Particles injected
into the peritoneal cavity were translocated mainly to mesentericlymph nodes and left sternal and right sternal lymph nodes. A
small percentage of particles went to the left TBLN.
ZeoliteThe oral bioavailability of silicon and aluminum in Zeolite A
was studied by Cefali et al. (1995). Twelve female beagle dogs
were administered a single 20-mg/kg dose of Zeolite A and blood
was sampled at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 h after dosing. The plasma samples were assayed for silicon and aluminumby graphite furnace atomic adsorption. No dogs displayed emesis but four had soft stool. The AUC (mg · h/L), Cmax (mg/L),
and Tmax (h) for silicon absorption was 9.5, 1.07, 7.9, respectively. The AUC (mg · h/L), Cmax (mg/L), and Tmax (h) for aluminum absorption was 342, 29, and 3.5, respectively. The AUC
and Cmax values were elevated after the addition of the silicon
containing compounds compared to the baseline and the AUC
was significantly elevated. There was no statistically significant
absorption of aluminum from the other aluminum-containing
compounds.
In a study by Cefali et al. (1996), the bioavailability of silicon
and aluminum in Zeolite A administered in either a capsule, anoral suspension, or an oral solution relative to an intravenous bolus infusion administered over a 1- to 1.5-min period was investigated. Twelve beagle dogs were given single doses of Zeolite
A and their plasma samples, drawn at 0 and 36 h, were analyzed
for silicon and aluminum concentrations by graphite furnace

Distributed for Comment Only -- Do Not Cite or Quote
SILICATES

atomic absorption. The plasma aluminum AUC values from theoral capsule and suspension were not statistically different fromthose during the control period. However, the aluminum AUCof the oral solution was statistically greater than the AUC of thecorresponding control period. The extent of absorption of aluminum form the oral dosage forms was less than 0.1% relative
to the intravenous infusion.
In Vitro Assays
Aluminum Silicate
Nadeau et al. (1987) tested Fiberfrax, an aluminum silicate, in
several in vitro assays for red blood cell (RBC) hemolysis, lactate dehydrogenase activity (LDH), β-galactosidase (β-GAL)
activity, lactic acid production, cellular ATP activity, and thecellular DNA contents. The mean length and diameter of thissample were determined to be 8.3 µm and 0.2 µm, respectively.
Approximately 60% of this Fiberfrax sample was nonfibrous.
For the hemolysis assay, RBCs from rats were isolated andexposed to 100, 250, 500, 750, or 1000 µg/ml of fibers for 1 h.
The percentage of release of hemoglobin was compared withthat of a fully lysed sample. The target cells for the other experiments were obtained by bronchoalveolar lavage from blackhooded rats. Each of the experiments tested both fresh cell monolayers and 1-day-old monolayers. Fiber samples were added tothe cultures at two doses, 33.3 µg/ml and 166.7 µg/ml. LDH activity was based on the formation rate of NADH at 340 nm. The
β-GAL activity was based on the measurement of p-nitrophenyl
release. The amount of metabolite released from PAMs (pulmonary alveolar macrophages) into the medium was the measurement of lactic acid production. PAMs were treated with 1 mlof dimethyl sulfoxide to release the nucleotides and the ATP wasmeasured later by a bioluminesence assay.
Fiberfrax particles produced no hemolytic activity at any concentration except 1000 µg/ml. Even at 1000 µg/ml, the particles
had very weak hemolytic properties with only 2.0% hemolysis. In fresh PAM monolayers, Fiberfrax was very cytotoxic at
166.7 µg/ml. The extracellular releases of LDH and β-GAL
were approximately 60% to 70% and 40% to 50%, respectively.
A low cell viability was confirmed by an 80% decrease in ATP
cell contents. Even at the lower dose, 33.3 µg/ml, a significant cytotoxic effect resulted, as judged by enzyme releases
and ATP cell contents. Again in the day-old cultures, Fiberfrax
was highly cytotoxic to PAM. LDH and β-GAL activities wereas great and ATP cell contents were significantly decreased.
At the lower dose, a moderate cytotoxic effect was observed.
Decreases in lactic acid production were more pronounced at
166.7 µg/ml. No significant effect on total DNA cell content
was noted in either the fresh or day-old cultures (Nadeau et al.
1987).
Attapulgite
Colony formation of human embryo intestinal cells (I-470)
was examined by Reiss, Millette, and Williams (1980). At a doseof 0.001 to 1 mg/ml of Attapulgite with fibers <2 µm, colony

63

formation was not modified. Colony formation was inhibited by
35% and 43% at doses of 2.5 and 5.0 mg/ml, respectively.
Oscarson, Van Scoyoc, and Ahlrichs (1981) added Attapulgite to a culture of bovine RBCs to study the extent of hemolysis. Saline was added to cultures as a control and in a separate
experiment, the polymer poly-2-vinylpyridine-N -oxide was also
added to study its inhibiting effects. No other details were given.
The concentration of Attapulgite that caused 50% hemolysis in
1 ml of a 3% solution of RBCs was determined as 0.06 mg Attapulgite/ml of silicate-erythrocyte-buffer suspension. A concentration of 0.2 and 1.0 µm/ml of polymer caused 20% and 3%
hemolysis, respectively. This was somewhat less hemolysis than
without the polymer.
Chamberlain et al. (1982) tested two samples, one with shortfibers and one with long fibers, of Attapulgite for their cytotoxicity in three cell lines: mouse peritoneal macrophages, humantype II alveolar tumor (A549) cells, and Chinese hamster V79-4
lung cells. Attapulgite samples of 50, 100, and 150 µg/ml−1 wereadded to mouse peritoneal macrophages for 18 h. The medium
and cell lysates were assayed for LDH activity. The control received no dust sample. In the second experiment Attapulgite,
100 µg/ml−1 and 200 µg/ml−1 , were added to A549 culturesand incubated for 5 days. The diameters of the cells were assessed for giant cell formation. The control treatment received
no dust. In the last experiment, the survival of V79-4 cells in
the presence of a series of concentrations of each dust was determined. Specific concentrations were not given. The cells anddust samples were incubated for 6 days and counted after the
incubation. The controls received no dust.
The mouse macrophages released 57.7% LDH from interaction with 150 µg/ml−1 of short fiber Attapulgite and was considered cytotoxic. However, the short fiber sample was consideredinert to the A549 cells and V79-4 cells. The long fiber Attapulgite
was cytotoxic to all three cell types. It was noted by investigators that mouse peritoneal macrophages are sensitive to both
fibrogenic and carcinogenic dusts; whereas nonmacrophage celllines such as V79-4 and A549 cells are insensitive to fibrogenic
dusts but sensitive to the fiber morphology of carcinogenic dusts(Chamberlain et al. 1982).
Gormley and Addison (1983) investigated the cytotoxic effectof Attapulgite with a particle size of 2.6 µm. Clay suspensions,
20 and 80 µg/ml, were added to P388D1, a macrophage-type
cell line for 48 h. Three sets of controls were included: a positive control, 20 µg of quartz DQ12 /ml; and two negative controls, 80 µg of TiO2 /ml, and an undusted set of cultures. The
following assessments were made: cell viability; the activity of
LDH; the activity of p-nitrophenyl-N -acetyl-β-D-glucosamide;
L-(+)-Lactic acid production; and total cellular protein concentrations. Cellular viability was expressed as a percentage of thetitanium dioxide control (100.0%) ± the standard deviation.
The 20-µg/ml dose of Attapulgite produced a 65.8% ± 9.2%
viability and the 80 µg/ml dose produced a 30.9% ± 17.4%
viability. Cellular LDH activities fell with decreasing cell viability, whereas the percentage of LDH in the medium increased.

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64

COSMETIC INGREDIENT REVIEW

Similar results were seen with glucosamidase. Also, the amountof lactate produced decreased as cell viability decreased. However, little change in the total cellular protein was recorded.
The induction of squamous metaplasia in tracheal organ cultures was investigated by Woodworth, Mossman, and Craighead (1983). Suspensions of Attapulgite at concentrations of
1, 4, and 16 mg/ml were added to the mucosal surface of thetracheal explants for 1 h. After experimental treatments, extracts were transplanted to another surface more suitable forcell attachment. Mucocillary differentiation was maintained for
4 weeks and the explants were examined at 2, 4, and 6 weeks after exposure to Attapulgite. The extent of squamous metaplasia
was evaluated by SEM (scanning electron microscope). The explants were labeled with [3 H]-thymidine and the labeling index
was scored. Four weeks after exposure to Attapulgite, the explants underwent both proliferative and metaplastic alteration.
Attapulgite induced an increase in metaplasia at low doses (1.0
and 4.0 mg/ml), but the increase was not statistically significant.
The labeling index was also increased slightly but statisticallysignificant. SEM was used to determine the association of fibers
with metaplastic lesions. Most fibers aggregated at the marginsof the explant, although small numbers of individual fibers were
distributed along the mucosal surface. These fibers either rested
on nonciliated cells or protruded into the mucosal surface. They
were often encompassed by accumulations of epithelial cells.
Metaplastic foci tended to be small. Many foci associated withthe lesions but some were located at sites where no lesions could
be seen.
The binding capacity, in vitro cytotoxicity, and percentageof hemolysis were investigated in a study by Harvey, Page,
and Dumas (1984). Binding assays were carried out using the
known carcinogens benzo(α)pyrene (B(α)P), nitrosonornicotine(NNN), and N -acetyl-2-aminoflurene (NAAF) and 2 mg/ml of
Attapulgite. A 2% suspension of sheep erythrocytes were added
to 30 mg of Attapulgite and incubated for 50 min. Cytotoxicity
was measured using 1000 µg of Attapulgite and macrophagelike P399D1 cells and using the Trypan blue dye exclusion
method. Hemolysis was calculated by measuring the opticaldensity at 540 nm. All experiments included the positive control
UICC chrysotile A and the negative control titanium dioxide.
Chrysotile binds significantly more to all three carcinogens thanthe other fibers ( p < .005) except Attapulgite. Attapulgite andchrysotile had very comparable binding capacities. Again Attapulgite and chrysotile had the greatest hemolysis and cytotoxicity compared to the negative control. On a scale of 1 to 5, 5 being
the greatest, Attapulgite scored a 3.72 and 4.26 in hemolysis andcytotoxicity, respectively.
The cellular interactions between Attapulgite and rat hepatocytes were examined in a study by Denizeau et al. (1985a).
Primary cultures of rat hepatocytes were exposed to 10 µg/ml
of Attapulgite fibers for 20 h. Ultrastructural analysis was performed by transmission electron microscopy. Fiber length was
not indicated in this study. Fibers are phagocytized by the cells
and numerous phagolysosomes are distributed throughout thecytoplasm. The phagolysosomes also appear in the vicinity ofcharged vacuoles. Invaginations of the plasma membrane engulfing fibers and formation of vacuoles are identifiable. Deeper
in the cytoplasm vacuoles with various shapes show the presenceof fibers.
Beck and Bignon (1985) incubated leukemic mouse cells with
two samples of 10, 50, or 100 µg/ml of Attapulgite. Viable cellcounts were taken at 0, 24, 48, and 72 h. A positive control consisting of UICC amosite and untreated negative controls werealso used in this experiment. The majority of fibers in the Attapulgite samples were <1.0 µm. No evidence of cytotoxicity wasmeasured over the 72-h period. The results from the Attapulgite
samples were indistinguishable from the untreated controls.
The cytotoxic effects of Attapulgite on rabbit alveolar macrophages and rat pleural mesothelial cells were investigated by
Jaurand et al. (1987). Attapulgite samples with a mean fiber
length of 0.77 µm were added at concentrations 4 and 8 µg/cm2
to rabbit alveolar macrophage cultures for 4 and 20 h; control
cultures received medium with no fibers. Enzyme release, activity of cytoplasmic LDH and lysosomal β-GAL was tested. The
presence of LDH activity in cultures was the gauge of cytotoxicity and the presence of β-GAL was the gauge of cell stimulation.
Attapulgite at both concentrations was cytotoxic at 20 h. β-GAL
release percentages for Attapulgite and quartz after 20 h were
almost identical.
Again Attapulgite was added at concentrations of 1, 2, 4,
and 10 µg/cm2 to rat pleural mesothelial cells. The cell number
was determined daily with the use of a Nachet NS 1002 image
analyzer. Attapulgite was not cytotoxic except at 10 µg/cm2 . At
the lower doses, cell number increases were comparable to thatof the controls (Jaurand et al. 1987).
Nadeau et al. (1987) tested Attapulgite for its effects on cells
in several in vitro assays for RBC hemolysis, LDH activity,
β-GAL activity, lactic acid production, cellular ATP activity,
and the cellular DNA contents. The mean length and diameterof this sample were determined to be 0.8 µm and 0.1 µm, respectively. The same study was conducted on Aluminum Silicate andall protocol and procedures are explained under that section. Attapulgite particles produced no hemolysis except at 1000 µg/ml.
Even at 1000 µg/ml, the particles showed very weak hemolytic
properties with only 2.0% hemolysis. Analysis with the fresh
PAM monolayers revealed Attapulgite to be very cytotoxic at
166.7 µg/ml. The extracellular releases of LDH and β-GAL
were approximately 60% to 70% and 40% to 50%, respectively.
A low cell viability was confirmed by an 80% decrease in ATP
cell contents. Even at the lower dose, 33.3 µg/ml, a significant
cytotoxic effect resulted, as judged by enzyme releases and ATP
cell contents. Again in the day old cultures, Attapulgite was
highly cytotoxic to PAM. LDH and β-GAL activities were verylarge and ATP cell contents were significantly decreased. At thelower dose, a moderate cytotoxic effect was observed. Decreases
in lactic acid production were more pronounced at 166.7 µg/ml.
No significant effect on total DNA cell content was noted ineither the fresh or day-old cultures.

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65

SILICATES

Garcia, Dodson, and Callahan (1989) investigated the effectsof Attapulgite on cultures of human umbilical vein and bovine
artery endothelial cell monolayers. Chrysotile asbestos was alsostudied as a positive control. Rapid phagocytosis of Attapulgite
and chrysotile particulates was evident in endothelial cell monolayers. Attapulgite was markedly toxic according to a gradientof time-dependent and concentration-dependent endothelial cell
injury measured by specific 51 Cr release. Chrysotile was muchless toxic. Responses of bovine pulmonary artery and humanvein endothelial cells to fiber phagocytosis and fiber-induced
injury were similar. Fiber-mediated stimulation in human umbilical cell monolayers of the arachidonate metabolite prostacyclin paralleled endothelial injury. Attapulgite was stimulatory inthis experiment, whereas chrysotile was only weakly cytotoxic.
Superoxide dismutase and catalase produced significant protection against fiber-mediated endothelial cell injury. Chelation bydeferoxamine of elemental Fe in the fiber preparations was also
protective.
Perderiset et al. (1989) reported the hemolytic activity ofAttapulgite on human red blood cells at five concentrations(0.05, 0.1, 0.2, 0.4, and 0.5 mg/ml). Additional studies tested thehemolytic activity of dipalmitoyl phosphatidylcholine (DPPC)and bovine serum albumin (BSA)-treated Attapulgite (2 mg/ml).
The mean fiber length was <2 µm. The percentage of hemolysis was determined by measuring the absorbance of the supernatant at 540 nm. At 0.5 mg/ml, Attapulgite caused 82%
hemolysis. The maximum amount of BSA adsorbed was
70 ± 10 µg/mg of Attapulgite, and the maximum occurred at
an initial concentration of 200 µg/ml. For DPPC, the maximum amount of BSA adsorbed was 210 ± 14 µg/mg of Attapulgite, and the maximum occurred at an initial concentrationof 250 to 300 µg/ml. Both compounds reduced the hemo-

lytic effect of Attapulgite due to adsorption on the particle’s
surface.
Nolen, Langer, and Herson (1991) tested nine different samples of Attapulgite for their membrane-lysing activity using human RBCs. The HC50 (concentration of particulate in µg/ml
required to lyse 50% of the erythrocytes in a suspension containing 1.8 × 108 cells/ml) was determined quantitatively. Threesamples of Chrysolite were used as positive controls. No otherdetails of the experiment were given. The fiber characteristics
were determined by light microscopy and x-ray diffraction andthe HC50 values are presented in Table 9.
Attapulgite’s cytotoxicity was investigated in rat pleural
mesothelial cells (RPMCs) by Yegles et al. (1995). A suspension of 0.5 mg/ml of Attapulgite was added to RPMCs, and a3,(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) viability test and anaphase/telophase abnormalities
test were performed. The clay sample had no fibers measuring
greater than 4 µm. Cytotoxicity was expressed as the concentration that provides 75% of cell viability compared to untreatedcontrols (IC75 ). Attapulgite was only poorly toxic with an IC75
of >100 µg/cm3 . Untreated controls averaged about 3.4% of abnormal anaphases; no significant anaphase abnormalities wereseen with Attapulgite as well.
Bentonite
The hemolysis of human erythrocytes and methylene blue adsorption by two Bentonite samples were investigated by M’anyai
et al. (1969). A white Bentonite sample consisted of 50% illite,
25% quartz, and 25% Montmorillonite; the yellow Bentonite
sample consisted of predominately Montmorillonite. The data
in Table 10 show that the hemolytic effect varied as a functionof both of the amount of clay (mg) and the surface area (m2 ).

TABLE 9Fiber characteristics of nine Attapulgite samples tested for their membranolytic activity using
human red blood cells (Nolen, Langer, and Herson 1991)
Fiber length (µm)
SampleFiber character<1.0

1.1–5.0

5.1–10.0>10.0

HC50 ∗ (µg/ml)

1
2
3
4
5
6
7
8
9
Chrysolite 1
Chrysolite 2
Chrysolite 3

Fibrous
FibrousNonfibrousFibrous
FibrousNonfibrous
Nonfibrous
NonfibrousFibrous
Fibrous
Fibrous
Fibrous

71.5
92.7
90.2
78.0
75.1
91.1
83.4
83.1
59.4
77.2
84.9
88.8

26.3
7.1
9.3
21.3
22.4
8.7
16.6
16.8
37.5
20.5
13.6
10.6

1.7
—
0.3
0.7
2.0
0.1
—
—
2.6
1.8
0.6
0.4

0.5
—
0.3
0.2
0.6
0.1
—
—
0.6
0.5
0.4
0.2

400
Inactive
746
211
369
76
83
109
51
41
82
59

∗
The HC50 is the concentration of silicate clay (in µg/ml) required to lyse 50% of the erythrocytes in a
1.8 × 108 cells/ml suspension.

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66

COSMETIC INGREDIENT REVIEWTABLE 10
Hemolysis and methylene blue adsorption results (M’anyai et al. 1969)
50% hemolysis in 1 mlof a 2% erythrocyte
suspension as function of:MineralBentonite
Bentonite
Montmorillonite
Montmorillonite
KaolinKaolinKaolinKaolinSampledescription

Amount of clay(mg)

Surface area ofclay (m2 )Amount ofmethylene blue
adsorbed by 1 m2
clay surface
(mg)

White
Yellow
Ca-substituted+
Quartz

1.66
1.0
5.0
0.8
2.0
1.5
4.0
5.0

0.039
0.135
0.50
0.02
0.06
0.07
0.06
0.115

3.59
2.13
1.46
—
1.09
1.60
0.12
0.19

Fat
White
Pink

Beck and Bignon (1985) dosed peritoneal macrophages with
two samples of Bentonite and the triphenyltetrazolium chloride(TTC) reduction, LDH activity, and methylene blue adsorption
were used to assess cytotoxicity. One sample of Bentonite contained 3% SiO2 and the other 34%. Bentonite inhibited TTC reduction similar to the fibrogenic dusts such as quartz. However,
the extracellular LDH activity was not increased and methylene
blue adsorption was very high.
Hatch et al. (1985) examined the cytotoxicity of Bentonite
to rabbit alveolar macrophages. The alveolar macrophages wereincubated with 1.0 mg/ml of Kaolin for 20 h at 37◦ C. Control
cultures received 1.0 mg/ml of TiO2 . The viability percentage ofthe macrophages and the ATP content of the cells as index of cytotoxicity were determined. Bentonite caused a large reduction
in both the viability and ATP levels. The viability index and ATP
levels were presented as percentage reductions and were 64.7%
and 92.0%, respectively. Controls figures were 18.3% and 0.7%,
respectively.
TTC reduction, LDH activity, and methylene blue adsorption
were measured as an index of cytotoxicity in a study by Adamis
et al. (1986). Bentonite was added to peritoneal macrophages
obtained from rats. No specific dose of Bentonite or other details were stated. TTC reduction was much greater and proved
Bentonite to be cytotoxic. Extracellular LDH was almost half
for Bentonite compared to control values. Methylene blue adsorption was significantly higher for Bentonite.
Murphy, Roberts, and Horrocks (1993a) investigated the cytotoxicity of Bentonite to human umbilical vein endothelial(HUVE) cells, undifferentiated N1E-115 neuroblastoma cells,
and ROC-1 oligodendrogial cells. Indices of cytotoxicity usedin this study were morphological examination, LDH activity,and fatty acid release. A suspension of Bentonite (1 to 2 µm
in fiber length) was added to the cultures at concentrations of
0.1, 0.03, and 0.01 mg/ml and incubated for 1, 6, and 24 h.

Following incubations, the cells were examined morphologically. The medium and cells were extracted for free fatty acidquantitation. LDH activities were assayed after 24 h of incubation at a Bentonite concentration of 0.10 mg/ml.
Bentonite did not lyse ROC-1 oligodendrogial and the neuroblastoma cells and did not cause a dose-dependent increasein fatty acids at 24 h. No significant increases in LDH activity were detected utilizing any of these cell lines. However,
Bentonite caused a dose-dependent increase in fatty acid concentrations only after 24 h of incubation. A 4.5-fold increasein fatty acid concentrations over control values was calculated.
Increases over control activities of LDH were 141% with Bentonite. Within 1 h, Bentonite associated with the plasma membrane of HUVE cells and the morphology was drasticallychanged after treatment (no details given). Cell lysis was also apparent with treatment. After trypan blue staining, 94% of HUVE
cells were nonviable with Bentonite treatment (Murphy, Roberts,
and Horrocks 1993a).
In a separate study by Murphy et al. (1993b), the cytotoxicity
of Bentonite was examined in two cell lines: primary murine
spinal cord neurons and differentiated N1E-115 neuroblastoma
cells. A clay suspension with a concentration of 0.1 mg/ml wasadded to the cultures. The neuronal cells were incubated for
1 h with Bentonite. Photomicrographs were taken at 5, 15, and60 min following treatment. For the N1E-115 cells, incubation
lasted 18 h and photomicrographs were taken at 5 and 15 min and3, 6, and 18 h after the treatment. Morphological changes wereobserved using a phase contrast microscope. Within 5 min, clay
particles were observed on the neuronal cell bodies. Cell bodies
appeared granular within 15 min. The cells were completely
lysed after 60 min and there was no evidence of any remaining
cell bodies or processes. Cell membrane contact was apparent
after 5 min in N1E-115 cultures. No morphological changes
were apparent at this point. At 18 h, the cells were covered with

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67

SILICATES

clay but cellular processes remained intact. N1E-115 cell lysis
did not occur and no cytotoxicity was recorded as a result ofBentonite treatment.
Calcium Silicate
Hunt, Pooley, and Richards (1981) tested three samples ofCalcium Silicate (A, B, and C) for biological reactivity in three
in vitro test systems. Table 11 presents the differences in SiO2
and Al2 O3 percentages between the three samples.
In the first test system, 50, 100, 150, and 200 mg of the threesamples of Calcium Silicate, UICC chrysotile (positive control),and titanium dioxide (negative control) were added to rabbit
erythrocytes. The cultures were incubated for 50 min. The percentage of hemolysis was calculated. Rabbit erythrocytes werealso incubated with 10, 30, and 50 mg heated, crushed samplesof Calcium Silicate to calculate the percentage of hemoglobin
binding. In the second study, rabbit alveolar macrophages wereincubated with 5 mg of the Calcium Silicate samples for timeintervals up to 60 min. The results were expressed as total viable
cells. In the third study, sonicated Calcium Silicate samples (100to 2000 µg) were added to rabbit lung fibroblasts. On days 7,
10, 17, and 24 after treatment, the cultures were analyzed forcellular DNA, protein, other cellular material, and hydroxyproline. Cytological studies on the same cells were carried out using
dust concentrations of 50 to 400 µg and staining the cultures tovisualize reticulin fibers.
In order to obtain 20% hemolysis, 0.4 mg of chrysotile, 2.8 mg
of A, 25.0 mg of B, and 15.0 mg of C are required. Titanium
dioxide did not produce 20% hemolysis at any concentration.
Sonication of all samples enhanced hemolysis and a “respirable”
preparation of A had the same hemolytic activity as chrysotile.
Sample B binds more hemoglobin than A or C but not more thanchrysotile. Samples B and C had enhanced hemolytic activity
when heated above 300◦ C. Heating had no effect on sample
A. All samples produced similar macrophage mortality and atconcentrations of 5 mg, only 60% of the cells were surviving at
60 min. Chrysotile at 5 mg resulted in a 20% viability. Samples A
and B produced greater DNA and protein concentrations at day
7. However, sample A induced greater protein concentrations
at day 24 with normal hydroxyproline levels. Sample B at day
24 had decreased concentrations of protein and hydroxyproline
with an increase in mineral concentration. Sample A produced
few changes in fibroblast morphology and reticulin deposits.
TABLE 11
Aluminum and Silicon content in Calcium
Silicate samples used in biological reactivity
study (Hunt, Pooley, and Richards 1981)
Calcium Silicate
sampleSiO2 %Al2 O3 %

A
B
C

57.3
52.3
53.7

2.6
4.4
1.0

TABLE 12
Sample characterisitcs of five Calcium Silicates tested forhemolytic activity in vitro (Skaug and Gyseth 1983)
SampleCaSi A, natural
wollastonite
CaSi B, natural
wollastonite
CaSi C, synthetic
wollastonite
CaSi D, synthetic
tobermorite
CaSi E, synthetic
tobermorite

Chemical formula

Fibrous
SiO2 % character

CaSiO3—+++

CaSiO3

2+

CaSiO39−

Ca5 Si6 O17 · 2.5 H2 O

10−

Ca5 Si6 O17 · 2.5 H2 O
Ca6 Si6 O17 (OH)2

2+

Sample B produced sparse and irregular deposition of reticulin(Hunt, Pooley, and Richards 1981).
Skaug, Davies, and Glyseth (1984) tested five Calcium Silicate dust samples for hemolytic activity in vitro. Electron microscopy and x-ray diffractions techniques were used to characterize the Calcium Silicates and the results are presented inTable 12. The Calcium Silicate samples A to E, chrysotile B(positive control), and titanium dioxide were added to RBCs atconcentrations of 0, 5, and 10 mg/ml. The effect of sonicationof the dust samples and the addition of 30 mM CaCl2 , EDTA,
and EGTA were also investigated. Sample E produced the greatest hemolysis at nearly 40%. The hemolytic activity of the synthetic Calcium Silicate samples were greater. In all experiments,
greater dust concentrations increased hemolysis. Sonication increased the hemolytic activity of the synthetic samples but had
no effect on the natural samples. The 30 mM CaCl2 increased
the hemolysis of samples D and E, but not C. EDTA did notdecrease hemolysis for samples D and C, and EGTA did notinhibit hemolysis of samples B, C, D, and E.
Five samples of Calcium Silicate also were used to test cytotoxic effects on mouse peritoneal macrophages in vitro. Calcium
Silicate concentrations of 0, 20, 40, and 60 µg/cm3 were added
to mouse peritoneal macrophages for 18 h. The medium and celllysates were assayed for LDH and β-glucuronidase (β-GLUC).
The positive-control dust utilized was DQ12 quartz standard andthe negative-control dust was magnetite. Characterization of thefive samples were carried out by means of x-ray diffraction andscanning electron microscopy. The results of the mineral characterization are presented in Table 13. The samples A, B, C, and D
had little effect on LDH release but sample E, the fibrous tobermorite, was clearly cytotoxic. Samples A and B caused releaseof large levels of β-GLUC. Sample E also caused the releaseof significant amounts of β-GLUC due to its cytotoxicity. Samples C and D caused the release of amounts comparable to thenegative controls (Skaug, Davies, and Glyseth 1984).

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68

COSMETIC INGREDIENT REVIEWTABLE 13
Mineral characterization of five samples of Calcium Silicate used to test cytotoxic effects on mouse peritoneal
macrophages in vitro (Skaug, Davies, and Glyseth 1984)
SampleA
B
C
D
E

Description

Chemical formula% SiO2 added

Presence of fibers

US wollastonite
Natural wollastonite
Synthetic wollastonite
Synthetic tobermorite
Synthetic tobermorite and xonotlite

CaSiO3
CaSiO3
CaSiO3Ca5 Si6 O17 · 2.5 H2 O
Ca5 Si6 O17 · 2.5 H2 O
Ca6 Si6 O17 (OH)2

—
2
9
10
2

+
+
−
−
+

Hectorite
In a study by Gormley and Addison (1983) mentioned earlier, the cytotoxic effects of Hectorite were investigated. The
Hectorite sample had a particle size of 2.8 µm. The proceduresare detailed in the study under the Attapulgite heading. Cellularviability was expressed as a percentage of the titanium dioxide control (100.0%) ± the standard deviation. The 20-µg/ml
dose of Hectorite produced an 83.4% ± 10.9% viability and the
80 µg/ml dose produced a 56.4% ± 13.3% viability. Cellular
LDH activities decreased with decreasing cell viability while
the activity of LDH in the medium increased. Similar results
were seen with glucosaminidase. Also, the amount of lactate
produced decreased as cell viability decreased. However, littlechange in the total cellular protein was recorded.
Banin and Meiri (1990) reported that they added Hectorite
to murine neuroblastoma cells at a concentration range of 70 to1000 µg/ml, although details were not provided. They concluded
that clear morphological signs of cell deterioration were evident
and, at the concentrations listed, an acute toxic effect was seen.
KaolinResults from a study by M’anyai et al. (1969) on the hemolysis and methylene blue adsorption by Kaolin are presented inTable 10.
Kaolin was heated to temperatures of 290◦ C, 350◦ C, 500◦ C,
650◦ C, 800◦ C, and 950◦ C and changes in the internal structureand surface properties were investigated and compared to alterations in hemolytic activity in vitro. The measurement of methylene blue adsorption and investigation of the crystal structure by
x-ray diffraction were made. In addition, Kaolin was added tohuman erythrocytes and the amount of lysed hemoglobin release was determined following an 1-h incubation. Complete
dehydration of Kaolin resulted in the formation of metakaolinite between the temperatures 500◦ C to 650◦ C. The formationof metakaolinite resulted in complete loss of hemolytic activity.
Heating to higher temperatures, 800◦ C and 950◦ C, resulted in
the formation of γ -Al2 O3 (mullite) or SiO2 (cristobalite), which
led to greater intensification of hemolytic activity. The extent
of hemolysis depended on the crystal structure and hydration of
the surface (M’anyai et al. 1970).

Oscarson et al. (1981) added Kaolin to a culture of bovine
RBCs to study the extent of hemolysis. Saline was added to cultures as a control and in a separate experiment, the polymer poly2-vinylpyridine-N -oxide was also added to study its inhibiting
effects. No other details were given. The concentration of Kaolinthat caused 50% hemolysis in 1 ml of a 3% solution of RBCs wasdetermined as 0.6 mg Kaolin/ml of silicate-erythrocyte-buffer
suspension. A concentration of 0.2 and 1.0 µM/ml of polymer
caused 50% and 20% hemolysis, respectively. This was somewhat less hemolysis than without the polymer.
Mossman and Craighead (1982) adsorbed 3-Methylcholanthrene (3MC) onto heat-sterilized preparations of Kaolin (4, 8,
and 16 mg dust/ml medium). The tracheas of female golden
Syrian hamsters were excised, and prepared for organ culturesand exposed to 3MC/Kaolin preparations. After 4 weeks in vitro,
the organ cultures were examined morphologically or implanted
subcutaneously into syngeneic weanling female hamsters. The
hamsters were palpated for tumors at 3-week intervals and any
masses >5 mm in diameter were excised. Animals with no tumors were killed at 105 to 110 weeks of age and the tracheal
implants were removed. The tracheal organ cultures and tumors
were fixed for microscopic examination. Explants exposed to
Kaolin had differentiated mucociliary epithelium for periods ofseveral weeks. In vitro the columnar mucosal cells acquired a
cuboidal configuration and the foci of the epithelial hyperplasia
appeared at sites where microscopically evident accumulationsof particles were deposited on the tracheal epithelium. No keratinizing squamous metaplasia was evident. Neoplasms developed in the tracheal implants exposed to 3MC-coated Kaolin.
Tumor development was dosage dependent. No sarcomas developed only carcinomas. In the highest Kaolin/3MC-treated group,
28% of the animals developed tumors. Tumors failed to develop
in tissues treated with Kaolin alone.
The comparative effects of Kaolinite (Kaolinite is the raw
mineral that comprises Kaolin) on cellular and artificial membranes were examined using three test systems: tracheal epithelial cells, sheep erythrocytes (RBCs), and preparations ofphospholipid-cholesterol vesicles in a study by Woodworth,Mossman, and Craighead (1982). Kaolinite doses of 0.003, 0.01,
0.03, and 0.1 mg/ml were added to tracheal epithelial cells for
24 h. Control cultures received no particulate. The 51 Cr release

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SILICATES

was determined by liquid scintillation. Spontaneous release wasdetermined from the control cultures. The second experiment,a hemolytic assay, combined RBC and Kaolinite doses of 0.1,
0.5, 1.0, 5.0, and 20.0 mg/ml were added at 37◦ C for 1 h. The
optical density was determined at 540 nm. One milliliter of the
preparation of liposomes (11.5 µg lipids) was added to 1 ml ofa Kaolinite suspension. After 1 h, the optical density of the mixture was measured at 380 nm. The percentage of CrO2−
4 release
was calculated. Control cultures received no particulate.
Kaolinite induced release of 51 Cr by tracheal epithelium wasalmost 50% at the highest dose. The cells phagocytized the particles, as demonstrated by SEM and phase-contrast microscopy.
This process was most evident after 24 h. Cells containing intracellular particles demonstrated retraction of lamellopoidal extensions, surface blebbing, and a change in morphology fromflattened to round.
A dose-dependent relationship between mineral concentration and hemolysis was demonstrated. Hemolysis was rapid. Approximately 50% of the RBCs were hemolyzed within 10 min.
SEM revealed remnants of RBCs in cultures with complete
hemolysis.
CrO2−
4 release at 10 mg/ml of Kaolinite was ∼35% after 1 h. A
dose-dependent relationship between particle concentration andCrO2−
4 release was again demonstrated (Woodworth, Mossman,and Craighead 1982).
In a study by Gormley and Addison (1983) described earlier, the cytotoxic effects of two Kaolins (K-1 and K-2) were
investigated. K-1 had a particle size of 3.2 µm, and K-2 had aparticle size of 3.9 µm. The procedures are detailed in the study
Gormley and Addison (1983) under the Attapulgite heading.
Cellular viability was expressed as a percentage of the titanium dioxide control (100.0%) ± the standard deviation. The
20-µg/ml dose of Kaolin (K-1) resulted in a 101.4% ± 6.7%
viability and the 80-µg/ml dose produced a 69.5% ± 6.5% viability. With a 20-µg/ml dose of Kaolin (K-2), viability was
93.6% ± 4.5%, with the 80 µg/ml dose, it was 60.0% ± 4.1%.
It may be noted that K-1 has a finer particle size but a smaller surface area as compared to K-2. Cellular LDH activities decreased
with decreasing cell viability, whereas the percentage of LDH
in the medium increased. Similar results were seen with glucosaminidase. Also the amount of lactate produced decreased
as cell viability decreased. However, little change in the total
cellular protein was recorded (Gormely and Addison 1983).
The cytotoxicity of Kaolinite toward mouse peritoneal macrophages was examined in a study by Davies et al. (1984). This
three-part study investigated whether or not respirable china clay
(Kaolinite) was cytotoxic toward macrophages in vitro, the components responsible for the toxicity, and the factors responsible
for the components toxicity. The assessment of toxicity was indicated by the activity of LDH assayed from the medium andcell lysates.
China clay dusts (60 µg/culture) from 12 separate drying
plants were added to mouse peritoneal macrophage cultures andincubated for 18 h. The medium and cell lysates were collected69

and assayed for LDH activity. All 12 cultures had changes thatindicated dust cytotoxicity. Between 19.5% and 60.0% LDH
was released from the cultures. Four other dust samples, three ofquartz (5,10,15, 20 µg/culture) and one of magnetite, were also
assayed. The cytotoxicity of quartz indicated a dose-dependent
relationship and was quite toxic. The magnetite dust had little
effect on LDH release.
Mineral composition of the dusts was determined using x-ray
diffraction analysis. A summary of the dust samples’ composition was as follows: Kaolinite (84% to 96%), mica (3% to 6%),
quartz (1%), and feldspar (0% to 7%). Due to the possibilityof other dust cytotoxicity, the biological effects of the ancillaryminerals and Kaolin was studied. Two high-purity Kaolins were
tested in the same method as above and were clearly cytotoxic
toward the macrophages. By x-ray diffraction, these two Kaolins
were both 98% pure Kaolin. The feldspar sample had lower activity than titanium dioxide, a material considered nonfibrogenic
and is used as a control dust in cell studies. The mica dust samples were cytotoxic but much lower than that of the Kaolin. By
mineral analysis, it was found that mica dusts had 34% Kaolinite. Quartz was ruled out as the cytotoxic agent due to the very
low concentrations (1%) in the initial experiment.
In a separate experiment, Kaolin pretreated with poly-2-vinyl
pyridine-N -oxide (PVPNO) (0.45 µg/mg), was added to mouse
peritoneal macrophages. (Note: PVPNO has been demonstrated
to reduce the cytotoxicity of Kaolin [Davies and Preece 1983]).
Electron micrographs were taken of the macrophages with andwithout the pretreated Kaolin for analysis of the factors causing
the toxicity. The ultrastructural alterations and number of particles within the cells appeared to be similar in both the treatedand nontreated cultures. It was concluded that PVPNO has noeffect on the inhibition of the uptake of Kaolin. Dust particles
were found adjacent to cell surfaces and in membrane-boundintracytoplasmic vesicles. However, no particles penetrated orwere seen penetrating the nucleus and no lysed cells were seen.
In the last set of experiments, the physical structure of Kaolin
and how it relates to dust toxicity was studied. Four componentsof Kaolin’s structure were examined: gibbsite or mica-like surfaces, positively charged edges, negative charged particles, andan amorphous ‘gel’ coating on kaolinite. Transmission electron micrographs of gibbsite or mica-like surfaces indicated
low toxicity and were ruled out as a possible marked toxic
factor. A colloidal gold decoration technique was to study the
positively charged edges of Kaolinite. Gold binds to the positively charged particles of Kaolinite and treatment of polyacrylic acid abolishes the gold decoration. In this study, mouse
peritoneal macrophages were incubated with polyacrylic treatedKaolin (120 µg/culture). Only a small drop in the cytotoxicity ofKaolin was observed. The electrophoretic mobility of negatively
charged Kaolin particles was also studied. Increased amounts ofammonium chloride produced a significant decrease in electrophoretic mobility. It is important to note that the greater concentrations did not produce negatively charged Kaolin particles.
These same aluminum-treated Kaolins were added to mouse

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70

COSMETIC INGREDIENT REVIEW

peritoneal macrophages (120 µg/culture) and the cytotoxicity
changed very little based on the amount of LDH activity released. The last experiment examined the effect of the amorphous ‘gel’ coating of Kaolin and its cytotoxicity. Plasma-ashingand the same LDH assay were performed on the samples. The
first group, Kaolin (40 mg/cm3 ), was plasma-ashed after 24 hand no effect was observed. Plasma-ashing after 72 h did reduce cytotoxicity. The second group of Kaolin dusts were mixed
with formalin-fixed lung tissue and then immediately plasmaashed. The cytotoxicity was not reduced. The last groups included Kaolin recovered from air-dried lungs of Fischer rats
exposed to china clay dust (10 mg/m3 ) for 40 h/week for 1 year,
left for 1 year, then ashed to a constant weight. Inhalation ofthese dusts was significantly less toxic. Reductions in cytotoxicity was probably due to alterations in the surface coating ofKaolin (Davies et al. 1984).
Beck and Bignon (1985) dosed peritoneal macrophages witha sample of Kaolin and the TTC reduction, LDH activity, andmethylene blue adsorption were used to assess cytotoxicity. The
sample contained 30% SiO2 . The results from this study classified Kaolin as an inert dust and nontoxic. Methylene blue adsorption was slight.
Gormley, Kowolik, and Cullen (1985) used luminoldependent chemiluminescence (CL) to assess the in vitro production of reactive oxygen species by human neutrophils andmonocytes after exposure to Kaolinite. Either opsonized or
nonopsonized Kaolinite dust was added to either neutrophil ormonocyte suspensions and luminol. The suspensions were assayed for CL and measured in millivolt. Concentrations of dust
ranged from the maximum of 3 mg/ml downwards. A control
suspension of zymosan (2 mg/ml) was also assayed for CL production. Neutrophils challenged with opsonized dust had relatively low dose-dependent CL production compared to controls.
However, when neutrophils challenged with nonopsonized dust,
CL production peaked at 67%. Again dose-dependent responses
were obtained when monocytes were tested. However, monocytes had a greater CL response in the presence of opsonized
dust. These results were the reverse of the earlier neutrophil responses as a very low monocyte CL production was obtainedwith nonopsonized dust.
In a study by Wallace et al. (1985), the cytotoxicity of nativeand surface-modified Kaolin and the effect of pulmonary surfactant were studied. Cell membrane damage and cytotoxicity were
measured by the release of alveolar macrophage cytoplasmic enzyme LDH, the lysosomal enzymes β-n-acetylglucosaminidase(β-NAG) and β-GLUC, and sheep blood cell hemolysis. Dipalmitoyl lecithin (DPL) emulsions made from synthetic L-αlecithin β,γ -dipalmitoyl were added to Kaolin to produce a
concentration of 7.5 mg dust/ml. Controls of saline and Kaolin
without DPL were also utilized. For the hemolysis assays, themixtures were resuspended in phosphate-buffered saline (PBS)
at a concentration of 2.0 mg dust/ml PBS.
Fresh sheep blood erythrocytes were mixed with dust suspensions in concentrations of 0.1 to 1.0 mg/ml. Untreated Kaolin

and DPL-treated Kaolin erythrocytes were incubated for 1 h
at 37◦ C. Negative controls were made with erythrocytes in PBS
and positive controls were made by lysing erythrocytes. All samples were read at 540 nm using a spectrophotometer and thepercentage of lysis was calculated. The lecithin treated Kaolin
suppressed erythrocyte activity to near “background levels.” Thehemolysis value for the maximum nontreated Kaolin concentration (1 mg/ml) was 42%, whereas the hemolysis value for thelecithin-treated Kaolin at the same concentration was 2%. Adsorption isotherm data estimated that 0.1 mg Lecithin/mg Kaolin
would provide full surface coverage and suppress the hemolytic
capacity to 97% lower than the native Kaolin.
In the second experiment of the same study, alveolar macrophage enzyme release studies were carried out using macrophages from Sprague-Dawley rats. Untreated Kaolin and DPLKaolin samples at a concentration of 1 mg/ml were mixed withmacrophages and incubated for 2 h at 37◦ C. The results weresimilar as in the above experiment. The nontreated Kaolin caused
release of enzymes: 570% LDH, 600% β-GLUC, and 570%
β-NAG of the control values. The treated Kaolin did not cause
the release of these enzymes. These results imply that Kaolin
damages erythrocytes and macrophages through cell membrane–
dust surface interactions and that pulmonary surfactants canabsorb the mineral surfaces for a short time (Wallace et al.
1985).
Mossman and Be’gin (1989) conducted a study in which
Kaolin samples were coated with the enzymes L-alphadipalmitoyl glycerophosphorylcholine (DGPL) and phospholipase A2 (PLA2 ) and the hemolytic potential of both coated andnoncoated samples were studied in vitro. The samples were incubated with sheep erythrocytes and the optical density of thesupernatant at 540 nm was determined to measure hemoglobin
release. With increasing amounts of DGPL, neutralization of thehemolytic potential occurred at 75 to 85 mg DGPL/g of Kaolin.
The residual adsorbed value was 83.0 mg DGPL/g Kaolin. The
digestive removal of DGPL by Kaolin was measured at the applied specific activity of 0.96 units PLA2 per molecule DGPL
on Kaolin. Most of the produced lysolecithin remains adsorbed
at 2 h.
Banin and Meiri (1990) added Kaolinite to murine neuroblastoma cells at concentrations of 100 to 1000 µg/ml. Withinminutes, the Kaolinite increased the increasing permeability ofthe membranes, depolarized resting potential, and the maintaining action potentials in response to stimulation were lost. Within
30 min, the cells had alterations of morphological deterioration.
Microvilli retracted, the surface assumed an unruffled, smoothappearance, and large holes developed in the plasma membrane.
Murphy, Roberts, and Horrocks (1993a) investigated the cytotoxicity of Kaolinite using three cell lines: HUVE cells, undifferentiated N1E-115 neuroblastoma cells, and ROC-1 oligodendrogial cells. Indices of cytotoxicity used in this study weremorphological examination, LDH activity, and fatty acid release.
Exact experimental details are provided in the Bentonite section
under the same heading.

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Kaolinite did not lyse ROC-1 oligodendroglia and the neuroblastoma cells and did not cause a dose-dependent increase infatty acids at 24 h. No significant increases in LDH activity weredetected utilizing either of these cell lines. However, Kaolinite
increased fatty acid concentrations after 24 h of incubation in adose-dependent fashion. A 1.7-fold increase in fatty acid concentrations over control values was calculated. Increases overcontrol activities of LDH were 146% with Kaolinite. Within 1 h,Kaolinite associated with the plasma membrane of HUVE cells
and the morphology was drastically changed after treatment (nodetails given). Cell lysis was also apparent. After trypan blue
staining, 90% of HUVE cells were nonviable with Kaolinite
treatment (Murphy, Roberts, and Horrocks 1993a).
Kaolinite dust was tested for potential human leukocyte elastase (HLE)-inhibiting effects (Oberson et al. 1996). HLE inhibition was evaluated by incubating 15 nM HLE for 1 h in thepresence of 5 µg of Kaolinite. Suc(Ala)3 pNA was then added for
30 min. Activity was measured at 410 nM. The 5 µg Kaolinite
abolished (90% inhibition) the activity of 0.45 µg HLE.
Montmorillonite
Results from a study by M’anyai et al. (1969) on the hemolysis and methylene blue adsorption by Montmorillonite are presented in Table 10.
Oscarson, Van Scoyoc, and Ahlrichs (1981) added Montmorillonite to a culture of bovine RBCs to study the extent ofhemolysis. Saline was added to cultures as a control and in a separate experiment, the polymer, poly-2-vinylpyridine-N -oxide,
was also added to study its inhibiting effects. No other details
were given. The concentration of Montmorillonite that caused
50% hemolysis in 1 ml of a 3% solution of RBCs was determined
as 0.006 mg Montmorillonite/ml of silicate-erythrocyte-buffer
suspension. A concentration of 0.2 and 1.0 µM/ml of polymer
reduced hemolysis to 23% and 0%, respectively.
The comparative effects of Montmorillonite on cellular andartificial membranes were examined using three test systems—
tracheal epithelial cells, sheep erythrocytes (RBCs), and preparations of phospholipid-cholesterol vesicles—in a study by
Woodworth, Mossman, and Craighead (1982). Montmorillonite
doses of 0.003, 0.01, 0.03, and 0.1 mg/ml were added to tracheal
epithelial cells for 24 h. Control cultures received no particulate.
The 51 Cr release was determined by liquid scintillation. Spontaneous release was determined from the control cultures. A second experiment, a hemolytic assay, combined RBC and Montmorillonite doses of 0.1, 0.5, 1.0, 5.0, and 20.0 mg/ml at 37◦ C
for 1 h. The optical density was determined at 540 nm. Control
cultures received no particulate. One milliliter of the preparationof liposomes (11.5 µg lipids) was added to 1 ml of a Montmorillonite suspension. After 1 h, the optical density of the mixture
was measured at 380 nm. The percentage of CrO2−
4 release wascalculated. Control cultures received no particulate.
Montmorillonite induced release of 51 Cr by tracheal epithelium was almost 60% at the highest dose. The cells phagocytized the particles, as demonstrated by SEM and phase-contrast

71

microscopy. This process was most evident at after 24 h. Cells
containing intracellular particles demonstrated retraction oflamellopoidal extensions, surface blebbing, and a changed morphology from flattened to round.
A dose-dependent relationship between mineral concentration and hemolysis was demonstrated. Hemolysis was rapid. Approximately 50% of the RBCs were hemolyzed within 10 min.
SEM revealed remnants of RBCs in cultures exhibiting complete
hemolysis.
CrO2−
4 release at 10 mg/ml of Montmorillonite was ∼40% after 1 h. A dose-dependent relationship between particle concentration and CrO2−
4 release was again demonstrated (Woodworth,Mossman, and Craighead 1982).
In the Gormley and Addison study (1983) described earlier,the cytotoxic effects of three samples of Montmorillonite (CaM1, CaM-2, and NaM) were investigated. CaM-1 and -2 have calcium substitutions in their lattices whereas NaM has sodium
substitutions. Particle sizes ranged from 2.0 to 3.1 µm. The
procedures are detailed under the Attapulgite heading. Cellularviability was expressed as a percentage of the titanium dioxide
control (100.0%) ± the standard deviation. The 20-µg/ml doseof CaM-1 with particle size of 3.1 µm produced a 79.1% ±
19.2% viability and the 80-µg/ml dose produced a 51.9% ±15.6% viability; CaM-2 with a particle size of 2.5 µm produced viabilities of 21.2% ± 3.5% (20 µg/ml) and 13.1% ±
2.2% (80 µg/ml); and NaM with a particle size of 2.0 µm produced viabilites of 47.3% ± 7.4% (20 µg/ml) and 37.2% ±
4.6% (80 µg/ml). The sample CaM-1 had the largest surface
area, whereas sample NaM, had the smallest. Sample CaM-2
had the lowest viability percentage despite the median particle
size and surface area. Investigators attributed the marked toxicity of sample CaM-2 due to the presence of ∼1% of quartz and
10% cristobalite in the sample. Sample NaM, which also exhibited a greater toxicity, contained ∼5% quartz and ∼2% calcite.
Cellular LDH levels fell with decreasing cell viability whereas
the percentage of LDH in the medium increased. Similar results
were seen with glucosaminidase. Also, the amount of lactate
produced decreased as cell viability decreased. However, littlechange in the total cellular protein was recorded.
Gormley, Kowolik, and Cullen (1985) used luminoldependent CL to assess the in vitro production of reactive oxygen species by human neutrophils and monocytes on exposure
to Montmorillonite. Either opsonized or nonopsonized Montmorillonite (containing a calcium as its exchange ion) dust wasadded to either neutrophil or monocyte suspensions and luminol.
The suspensions were assayed for CL and measured in millivolt.
Concentrations of dust ranged from the maximum of 3 mg/ml
downwards. A control suspension of zymosan (2 mg/ml) was
also assayed for CL production. Neutrophils challenged with
opsonized dust resulted in relatively low dose-dependent CL
production compared to controls. However, when neutrophils
were challenged with nonopsonized dust, a marked response of
CL peak production at 114% was elicited. Again dose-dependent
responses were obtained when monocytes were tested. However,Distributed for Comment Only -- Do Not Cite or Quote

72

COSMETIC INGREDIENT REVIEW

monocytes elicited a slightly higher response in the presence of
opsonized dust. These results proved to be the reversal of the earlier neutrophil responses. A very low monocyte CL production
was obtained with nonopsonized dust.
Banin and Meiri (1990) reported a study in which Montmorillonite was added to murine neuroblastoma cells at a concentration range of 100 to 1000 µg/ml, but no details were given.
The authors concluded that clear morphological signs of cell
deterioration were evident and, at the concentrations listed, anacute toxic effect was seen.
Murphy, Roberts, and Horrocks (1993a) investigated the cytotoxicity of Montmorillonite to three cell lines: HUVE cells, undifferentiated N1E-115 neuroblastoma cells, and ROC-1 oligodendrogial cells. Indices of cytotoxicity used in this study weremorphological examination, LDH activity, and fatty acid release.
Exact experimental details are provided in the Bentonite section
under the same heading.
Montmorillonite did not lyse ROC-1 oligodendroglia and theneuroblastoma cells and did not cause a dose-dependent increasein fatty acids at 24 h. No significant increases in LDH activity
were detected utilizing either of these cell lines. However, Montmorillonite caused a dose-dependent increase in fatty acid levels
only after 24 h of incubation. A 10-fold increase in FA levels
over control values was calculated. Increases over control activities of LDH were 154%. Within 1 h, Montmorillonite associatedwith the plasma membrane of HUVE cells and the morphology
was drastically changed after treatment (no details given). Cell
lysis was also apparent with treatment. After trypan blue staining, 99% of HUVE cells were nonviable with Montmorillonite
treatment (Murphy, Roberts, and Horrocks 1993a).
In a study by Murphy et al. (1993b), the cytotoxicity of Montmorillonite was examined in two cell lines: primary murine
spinal cord neurons and differentiated N1E-115 neuroblastoma
cells. A clay suspension with a concentration of 0.1 mg/ml wasadded to the cultures. The neuronal cells were incubated for 1 h
with Montmorillonite. Photomicrographs were taken at 5, 15,
and 60 min following treatment. For the N1E-115 cells, incubation lasted 18 h and photomicrographs were taken at 5 and 15 min
and 3, 6, and 18 h after the treatment. Morphological changes
were observed using a phase-contrast microscope. Within 5 min,clay particles were observed on the neuronal cell bodies. Cellbodies appeared granular within 15 min. The cells were completely lysed after 60 min and there was no evidence of any
remaining cell bodies or processes. Cell membrane contact wasapparent after 5 min in N1E-115 cultures. No morphologicalchanges were apparent at this point. At 18 h, the cells were covered with clay but cellular processes remained intact. N1E-115
cell lysis did not occur and no cytotoxicity was recorded.
Montmorillonite dust was tested for potential HLE-inhibiting
effects (Oberson et al. 1996). HLE inhibition was evaluated byincubating 15 nM HLE for 1 h in the presence of 5 µg of Montmorillonite. Suc(Ala)3 pNA was then added for 30 min. Activity
was measured at 410 nM. The 5 µg Montmorillonite (98% inhibition) abolished the activity of 0.45 µg HLE.

Pyrophyllite
The cytotoxicity of Pyrophyllite dust on rat alveolar macrophages was investigated in a study by Zhang, Zhang, and Song
(1997). Cytotoxicity was measured by the potassium content of
the macrophages and the levels of LDH. Alveolar macrophages
were isolated from bronchi alveolar lavages of male Wistar
rats. These animals were divided into six groups based on the
dust concentrations. The groups were as follows: quartz(75.72 µg/ml) dust group; Pyrophyllite mine (PM) dust groupA, 200 µg/ml (75.72 µg/ml SiO2 and 30.42 µg/ml Al2 O3 ); PM
dust group B, 200 µg/ml (75.72 µg/ml SiO2 and 30.42 µg/ml
Al2 O3 ); Pyrophyllite carving mills (PCM) dust group A,
200 µg/ml (31.68 µg/ml SiO2 and 40.58 µg/ml Al2 O3 ); PCM
dust group B, 200 µg/ml (31.68 µg/ml SiO2 and 40.58 µg/ml
Al2 O3 ); normal control of saline. Both PM group B and PCM
group B were imitated groups of the natural dusts from themines used to study the toxicity of SiO2 and Al2 O3 . They did
not include the metals Fe, Cu, Ni, and Zn as did both samples A. The cell cultures were incubated at 37◦ C for 16 and22 h.
The LDH activity of quartz was greater than all other groups
except PM group A incubated at 22 h. When compared to thesaline controls, all exposed groups had significantly lower increases in LDH activity. Both the LDH activities of the PM dustgroups were greater than those of the PCM dust groups ( p < .5).
However, no differences between the PM groups A and B or between the PCM groups A and B were detected. The K+ content
of the saline controls was greater than all exposed groups. The
quartz group had the lowest concentrations of K+ followed by
the PM dust groups and then the PCM dust groups. Again, nodifferences between either A or B groups was observed. It was
concluded that Pyrophyllite dust exposure is cytotoxic to alveolar macrophages and people working in a PM have greater riskof respiratory problems than people working on PCMs.
Mineralogical analysis of the dust samples taken from themines was performed using an atomic absorption spectrophotometer. The SiO2 content was 37.9% higher in the PM groupthan in the PCM group 15.8%. Al2 O3 concentrations were lower
in the PM dust groups (15.2%) than in the PCM dust groups(20.3%). Toxicity due to metals in the samples A was ruled out.
The samples B did not include the metals and had similar LDH
activity as the samples A (Zhang, Zhang, and Song 1997).

Zeolite (Zeolite A)
Zeolite A at concentrations of 0.1 to 100 µg/ml was incubatedfor 48 h with normal human osteoblast-like cells. An inductionof a dose-dependent increase in DNA synthesis and the proportion of cells in mitosis occurred. This mitogenic action wasdependent on cell seeding density. Alkaline phosphatase activity
and osteocalcin release were also increased but no significant effect on collagen production per cell occurred. Zeolite treatment
increased the steady-state mRNA levels of transforming growth
factor β (Keeting et al. 1992).

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SILICATES

Zeolite (Clinoptilolite)
Total degradation of rat peritoneal macrophages incubatedwith Clinoptilolite dust particles occurred during 15- and 30-min
time periods at concentrations of 1.0 and 0.5 mg/ml, respectively. Dust particles measured <5 µm. Thirty-eight percent ofmacrophages and 57.5% of RBCs were killed within 30 min at
a Zeolite concentration of 0.25 mg/ml. Dose-dependent CL wasobserved in the first 10 to 20 s when luminol was added to thecultures. Catalase (30% to 50%) decreased the cytotoxic effects
of Zeolite, whereas ethanol, sodium azide, and mannitol had noeffect (Korkina et al. 1984).
Zeolite (Mordenite)
Syrian hamster and rat alveolar macrophages were exposed
to nontoxic concentrations of Mordenite and the reduction ofcytochrome c in the presence and absence of superoxide dismutase, and the amount of O2 released were indicators of cytotoxicity. Other fibrous particles were used as positive controls. Mordenite as compared to the positive controls was lessactive at comparable concentrations (Hansen and Mossman1987).
Zeolite (Nonfibrous Japanese Zeolite)
Japanese Nonfibrous Zeolite was incubated with two celllines, Chinese hamster V79-4 and A579 at concentrations ranging from 5 to 100 µg/ml. Two samples of erionite and a sampleof UICC crocidolite, a positive control, were also tested. Concentrations that inhibited plating were estimated using the LD50 .
Compared to the positive control and the erionite samples, theZeolite had a much greater LD50 value and was nontoxic in the
A549 assay (Brown et al. 1980).

ANIMAL TOXICOLOGY
Acute Oral
Calcium Silicate
Calcium Silicate FDA compound 71-41 was suspended in
0.85% saline and administered to 10 male rats by intubation.
Each animal that received a dose of 5000 mg/kg died within
24 h. Doses of 100, 500, 1000, 2000, 3000, and 4000 mg/kg
were selected to determine the acute LD50 using the LitchfieldWilcoxson method. Groups of 5 male rats were administered thedoses and were killed for necropsy. The LD50 was determined
as 3400 mg/kg; at the highest dose, necropsy findings included
bloody gastric mucosa with distension, hydrothorax, and congested lungs. In a second LD50 assessment, Calcium Silicate wasprepared as 24.1% (w/v) suspension and administered orally toa group of 10 male rats at a single dose of 5000 mg/kg. No
signs of toxicity or abnormal behavior were observed within a
7-day period. No deaths occurred. All animals were killed and on
necropsy no gross findings were observed. The acute oral LD50
was considered to be greater than 5000 mg/kg (Litton Bionetics,
Inc. 1974).

73

Hectorite
Five male and five female Sprague-Dawley rats were administered a single dose of 5 g/kg of the test article by gavage. The
animals were observed the day of dosing and 15 days after forgross and visible toxic or pharmacological effect. No such effects were seen and none of the animals died. All animals were
killed for necropsy. No findings were reported. The acute oral
LD50 was >5.0 g/kg of body weight (FDRL Inc. 1980b).
KaolinA report by the Federation of American Societies for Experimental Biology (1977) included an acute oral study in which
120 rats were fed doses of Kaolin ranging from 100 to 210 g/kg.
Fourteen rats were controls. Kaolin was inert and nonstatic except for the danger of bowel obstruction resulting in perforation.
The clinical signs were listlessness, anorexia, oliguria, hypothermia, and dyspnea. These were a pathological reaction fromoverdistension of the alimentary canal by an inert solid. The
number of fatalities and the incidence and advance of bowel obstruction along the small intestine were dose related. The dosethat killed 50% of the rats by bowel obstruction was 149 g/kg.
McClurg, Beck, and Powers (1980) fed a group of 10 maleSprague-Dawley rats a control diet plus 0.5 ml Kaolin 20%–
pectin 1%. The control diet was then fed for 48 h and 72 h laterstool samples were collected. The samples were analyzed forvolume, sodium, potassium, and fat content. The results were103% increase in sodium; 184% increase in potassium; fat excretion remained at baseline.
Magnesium Aluminum Silicate
Suspensions of 1 ml of Magnesium Aluminum Silicate atdoses of 100–2000, 5000,10000, 20000, and 50000 mg/kg wereadministered to a series of 37 mice. At the greatest dose, themortality rate was 33%. The LD50 was considered to be>50,000 mg/kg (Munch 1944).
Zirconium Silicate
In a study conducted by Stookey et al. (1967), the LD50 of
Zirconium Silicate was determined. Oral intubations of a 60%
aqueous slurry of Zirconium Silicate containing 1% carboxymethylcellulose to prevent settling was given to 80 albino mice.
Doses ranged from 70 to 200 gm/kg body weight. A dosage of
200 g of Zirconium Silicate per kilogram body weight was not
sufficient to create a 50% mortality rate in mice. Dosages greaterthan 200 g were not tested due to the limitations of the mousegastrointestinal tract. A 37.5% mortality rate was recorded forthe dosage of 200 g/kg of body weight.
Short-Term Oral
Bentonite
Carson and Smith (1982) fed Bentonite at concentrations 0%,
2.5%, 7.5%, or 10% to male weanling rats to determine themost effective level to overcome the effects of T-2 toxicosis.

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74

COSMETIC INGREDIENT REVIEW

Increasing the concentration of Bentonite resulted in significant
increases in body weight and feed consumption. The most effective concentration tested was 10%. Bentonite had no effecton the activity of nonspecific hepatic esterase.
The role of Bentonite in the prevention of T-2 toxicosis in rats
was further investigated by Carson and Smith (1983). Groups of
10 male Wistar rats were fed diets containing 5% Bentonite for
2 weeks and the feed consumption and growth were recorded.
Each diet was administered with or without 3 µg T-2 toxin/gof feed for 2 weeks. Bentonite reduced the decreases in final
body weight and feed consumption as compared to controls.
The livers from this test group were excised and assayed fornonspecific esterase (E.C.3.1.1.1). Five percent Bentonite hadno significant effect on the activity of this enzyme. In a second experiment, Bentonite was supplemented in the control dietat 2.5%, 5.0%, 7.5%, and 10%. Bentonite at 2.5% greatly increased feed consumption and final body weights and feeding.
Ten percent Bentonite overcame the toxicosis completely. In a
third study, rats were fed 0%, 5%, 7.5%, or 10% Bentonite for
2 weeks and then dosed with [3 H] T-2 toxin. The urine and feces
were collected at 21 h and tissues were excised for determinationof residual 3 H. Feeding Bentonite had little effect on the fractionof the dose excreted in the urine. Feeding 5%, 7.5%, and 10%
Bentonite resulted in significant increases in the fecal excretionof 3 H when compared to controls. Bentonite had no effect on
residual 3 H in the liver or kidneys but all concentrations reduced
residual 3 H in muscle. Rats fed 5% Bentonite had more 3 H in
the digesta in the small intestine and in the wall of the intestinal tissue when compared to controls. Intestinal transit time was
reduced as well.
Bartko et al. (1983) fed a group of five sheep a diet containing
0.15 g/kg body weight of Zeolite for 3 months. Other sheepreceived no additions to their normal diet. At the end of thestudy, no difference in health effects was found between the twogroups. The health effects included general behavior, total andacute acidity, content of volatile fatty acids in rumen contents,
hematological values, content of microelements, transaminase
activity, and acid-base homeostasis in the blood.
Magnesium Aluminum Silicate
Munch (1945) gave groups of 10 mice daily doses of either 5
or 10 g/kg of body weight orally for 10 days. Two days separated
the first five doses from the second five doses. No signs wereobserved in any mouse at any time when administered 5 g/kg.
The animals were killed and no pathological changes were seenat necropsy. No tissue was taken for further examination. One
mouse died after five doses of 10 g/kg and one mouse died afternine doses of 10 g/kg. Neither mouse had lesions at postmortem
examination.
This same author administered VEEGUM orally to 10 rabbits
for a total of 10 doses. The first four animals were given 5 g/kg
of body weight; the fifth animal was a control. The second fouranimals were given 10 g/kg of body weight; the fifth was also acontrol. No changes in body weight, no signs at toxicity, and no

deaths were recorded. All animals were killed and at necropsy
no lesions were seen in the stomach, liver, kidneys, or other viscera. No tissue was taken for microscopic examination (Munch
1945).
Zeolite (Clinoptilolite)
In a 148-day feed-lot experiment reported by McCollum andGalyean (1983), 48 cross-bred steers were fed a 70% sorghum
diet with Clinoptilolite substituted at 0%, 1.25%, and 2.5% of
the diet dry matter. No differences were found among treatments
in average daily weight gain, feed intake or feed efficiency.
Pond, Yen, and Crouse (1989) fed 32 castrated male pigs
various diets of calcium, iron, and Clinoptilolite to study tissuestorage of major and trace elements with the addition of Clinoptilolite. At day 84, all pigs were killed and analyzed. Dietaryconcentrations of calcium, iron, and Clinoptilolite had no effecton daily weight gain, daily feed intake, or the ratio of weight
gain:feed intake of growing pigs.
Zeolite (Clinoptilolite and Sodium Zeolite A)
Weanling Landrace × Yorkshire pigs were fed diets containing 3% Clinoptilolite with or without 150 ppm cadmium chloride or 3% Sodium Zeolite A with or without 150 ppm cadmium
chloride for 31 days. Pigs fed cadmium and Zeolites did not havedecreased hematocrit and hemoglobin values similar to those ofpigs fed diets without the Zeolites. Hepatic cadmium concentration was significantly reduced in animals fed with Clinoptilolite.
Hepatic iron was not affected significantly by either Zeolite; hepatic iron and zinc were decreased by dietary cadmium. Hepatic
zinc was increased by Sodium Zeolite A (Pond and Yen 1983b).
Zeolite A
Various diets containing no Zeolite, 0.3% Zeolite A, or 0.5%
Clinoptilolite were fed to cross-bred pigs for 6 weeks. The average daily weight gain, average daily feed intake, and feed:weightgain ratio were unaffected by supplementation of either Zeolite.
Energy utilization was improved by feeding diets containing
either Zeolite (Shurson et al. 1984).
Subchronic Oral
Magnesium Aluminum Silicate
The Food and Drug Research Laboratories (FDRL 1958a)
carried out a 90-day feeding study using 220 weanling albino
rats divided into five groups. The largest dose group consistedof 10 male and 10 female rats; control animals totaled 25 rats ofeach sex. A commercial ration was supplemented with 2%, 5%,10%, and 20% VEEGUM. Control diets were unmodified. Body
weight and feed intake were recorded daily and the efficiency of
feed utilization (EFU; gram gained per 100 g) was calculated.
Hematological examinations were made at 6 and 12 weeks on
half of the test group. Blood sugar and nonprotein nitrogen determinations and urine analyses were also completed. Four rats
in the 20% group, four rats in the 10% group, and control group

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SILICATES

were placed on a modified program to estimate the balance between the intake of dietary ash and the ash excreted. Rats fed the
20% diet were examined at 8 weeks and rats fed the 10% dietat 12 weeks. All animals were killed at the end of the 90-day
period. Liver, kidneys, spleen, heart, and adrenal glands weights
were determined. Microscopic examination of the liver, kidneys,
spleen, and portions of the gastrointestinal tract of four rats ofeach sex and control, 10%, and 20% groups were carried out.
The average body weights and net gains were not adversely
affected by the ingestion of VEEGUM up to 10% in the diet.
Growth was diminished slightly but with statistical significance( p = .05) when 20% VEEGUM was fed to both sexes. WithEFU corrections, only the 20% dose significantly lowered theobserved EFU value. One male rat of the 2% group died andone of each sex of the 10% group died. These rats had fibrinous exudates in the thorax, hemorrhagic lungs, and evidenceof respiratory infection at necropsy. Gross findings for the restof the animals revealed no significant abnormalities other thanin the lungs. The incidences of pulmonary lesions did not differ among controls and test animals. Organ weights fell within
normal limits. Hematological observations were within normal
limits, including the rats of the 20% group. Blood sugar andnonprotein nitrogen values were also within normal limits. Females of the 20% group had slightly increased values compared
to controls but still were in the normal range. Silicon content
of the spleens of control animals were about the same as in the
2% group. However, in the 5% and 10% groups, the silicon content was slightly increased. Microscopic examination disclosed
no abnormalities in the liver, kidneys, and gastrointestinal tract.
Ash data indicated that 81% of VEEGUM of the 20% group
was excreted and 73% of the 10% group was excreted (FDRL
1958a).
FDRL (1958b) fed two groups of four mongrel dogs, twofemale and two male for each group, a basal diet and a diet supplemented with 10% VEEGUM for 90 days. At 6 and 12 weeks,complete blood counts were made and blood sugar and nonprotein nitrogen were determined. Urine specimens were examinedat 12 weeks for acidity, sugar, albumin, and microscopic elements in the sediment. At the end of 90 days, all dogs were
killed for necropsy. Silicon content of the spleen was also determined. Body weight did not change despite a depression ofappetite with the addition of VEEGUM. No abnormalities wereseen upon hematological examination at the 6- or 12-week periods. Two of the test animals had slightly increased blood sugarat the end of the testing period. All other values for sugar andnonprotein nitrogen levels were normal. No difference in organ
weight was seen. Silicon concentration of the spleens of the test
animals were slightly elevated compared to controls (143 versus 103 mg/spleen). No microscopic lesions were compound
induced.
CTFA (1999b) reported that in feeding tests with dogs andrats ingesting large amounts of VEEGUM (10% of ration) for
90 days, all responses were negative and VEEGUM was considered nontoxic.

75

Magnesium Trisilicate
Page, Heffner, and Frey (1941) gave six white rats daily dosesof 0.6 g of Magnesium Trisilicate for 6 months. A litter wasborn and divided into two groups, a control and a treated group.
The treated group received Magnesium Trisilicate doses fromthe time of weaning that corresponded to a daily dose of 3 or
4 pounds for a healthy human. This litter was also mated. Tissues from the animals of the first and second generation were
examined microscopically. No evidence of tissue changes wererecorded.
Dobbie and Smith (1982) gave six male guinea pigs a suspension in tap water of 250 mg/L Magnesium Trisilicate over a
4-month period for 5 days each week. Atomic absorption spectroscopy established that the soluble Si in the suspension was
267 µmol/L. Normal tap water was given to six control animals 7 days a week and 2 days a week to the test guinea pigs.
At 4 months, all animals were killed for necropsy. The kidneys
were processed for microscopic examination. All six animals
had renal lesions that involved the distal nephron. Lesions of
the distal tubule were dilation or cystic change. Some tubules
were plugged with proteinaceous material. The interstitium of
the kidneys was expanded by chronic inflammatory cells andexcess collagen fibers. No lesions were seen in control animals.
Chronic Oral
Zeolite (Synthetic Zeolite A)
Groups of 50 male and female Wistar rats were fed 1, 10,100, or 1000 mg/kg of Synthetic Zeolite A in their diets for up to
104 weeks. Clinical signs, mortality, and gross and microscopic
lesions were recorded. No differences in body weight gain or
clinical parameters were observed between control and treatedanimals. Based on feed intake, the Zeolite intake of the 10-,100-, and 1000-mg/kg groups was 0.62, 6.1, and 58.5 mg/kg
body weight/day for males and 0.65, 6.53, and 62.2 mg/kg bodyweight/day for females, respectively. No significant treatmentrelated lesions were observed in any of the organs examined andthere was no effect on the types or incidence of any neoplasticchanges seen (Gloxhuber et al. 1983).
Acute Parenteral
Aluminum Silicate
Musk et al. (1988) exposed Syrian golden hamsters to saline
suspensions of Aluminum Silicate at 3.75 and 0.75 mg/100 gbody weight by intratracheal instillation and sacrificed the animals at day 1. Their lungs were lavaged and the lavage fluid wascharacterized using cellular and biochemical indicators (lactic
dehydrogenase, albumin, macrophages, polymorphs, and RBCs)
of pulmonary damage. Either dose did not alter the biologicalparameters tested in comparison to those animals only exposed
to saline.
Lemaire et al. (1989) gave Fiberfrax, an aluminum silicate, byintratracheal instillation at doses of 1, 5, and 10 mg to groups of

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76

COSMETIC INGREDIENT REVIEW

five rats. The details of this experiment are explained by Lemaire
et al. (1989) under the Attapulgite heading in this section. The
average length of Fiberfrax fibers were 8.3 µm and <50% were
under 5 µm. The significant inflammatory response was mainly
numerous lymphocytes and epithelioid giant cells. The lesions
were located predominantly around the terminal bronchioles.
Areas of early fibrosis were seen in the lesions. Every test animal
developed type C lesions, described above. A dose-dependent
reaction was suggested due to more extensive lesions seen inanimals dosed with 10 mg. The bronchoalveolar lavage fluid had
macrophages as the predominant cells followed by neutrophils
and then by lymphocytes.
Pigott and Ishmael (1992) studied the effects of intrapleuralinjections of Aluminum Silicate in rats. A single intrapleural injection of 20 mg of four Aluminum Silicate samples (Saffil, aged
Saffil, aluminosilicates A and B) and chrysotile A asbestos wasadministered to dose and control groups consisting of 24 rats ofeach sex. The control group received only a saline injection. The
predominant length of the fibers in each sample were Saffil, 10 to
20 µm; aged Saffil, 20 to 40 µm; aluminosilicate A, 20 to 40 µm;
and aluminosilicate B, 0 to 10 µm. Each rat was allowed to live
out its lifespan or until it appeared distressed until 85% mortality was reached. All animals, were then killed and organs weretaken for microscopic examination. Reactions to both forms of
Saffil were very similar. In almost all animals, a minimal focal
chronic pleurisy/fibrosis was minimal with adhesion formation.
Pericardial adhesions and mesothelial proliferation with some
Saffil fibers were seen. The reactions to both aluminosilicate
samples were very similar. Minimal to moderate focal chronic
pleurisy/fibrosis was often associated with mesothelial proliferation. Aluminosilicate B caused three malignant mesotheliomas,
one pleural and two peritoneal. A benign testicular mesothelioma was seen in one rat dosed with Saffil, two dosed withaged Saffil, and four dosed with aluminosilicate A. Incidencesof tumors are presented in Table 14.

Attapulgite
Pott et al. (1987) injected three samples of 25 mg of Attapulgite dust intraperitoneally into 40 Wistar rats. Electron microscopy of the sample revealed 37.5% of fibers <2 µm longand 70.0% <5 µm. All animals were observed until they diedeither spontaneously or were killed. Saline was injected into 80
control animals. The time required to produce the first tumor in
the rats was 257 days and the tumor incidence rate was 65%.

Stanton et al. (1981) reported that two groups of 30 to 50 female Osbourne-Mendel rats received a single direct application
to the left pleural surface by open thoracotomy of 40 mg of
one of two Attapulgite samples. The samples were 90% purewith quartz being the other component. One dose consisted offibers >4 µm and the other contained no fibers >4 µm. The rats
were killed at the end of 2 years. Pleural sarcomas were seen in
2/29 rats. The incidences of pleural sarcomas in the untreatedgroups were 3/491 and 17/615 of the rats receiving the pleural implants of Attapulgite. Of rats receiving UICC crocidolite,
14/29 developed pleural mesotheliomas.
Be’gin et al. (1987) delivered Attapulgite with a mean fiber
length of 0.8 µm and diameter of 0.02 µm to the lungs of sheepby bronchioscopic cannulation. The tracheal lobe of 16 sheep
was subjected to a single exposure of 100 mg of Attapulgite
in 100 ml of saline. A bronchoalveolar lavage (BAL) was conducted at 2, 12, 24, 40, and 60 days, and necropsy was conducted
on day 60. Total BAL cells, macrophages, and neutrophils, fibronectin content, and LDH and β-GLUC activity were examined. Nine samples of the tracheal lobe of the lung wereobtained each time for microscopic examination. The controls
were saline-exposed sheep and had no changes in BAL or pulmonary morphology. The total BAL cells/ml and subpopulations
increased significantly above control numbers at days 12, 24, and40 but returned to control levels by day 60. Albumin and procollagen III did not differ from controls, whereas fibronectin, LDH,
and β-GLUC activities were significantly above the controls.
Microscopic examination revealed infiltrates that were predominantly alveolar and peribronchial lesions. Macrophagic alveolitis with minimal airway distortion was seen. Three sheep had
lesions of peribronchiolar alveolitis.
Jaurand et al. (1987) injected samples (20 mg/ml of 0.9%NaCl) of Attapulgite fibers with the median length of 0.77 µm
into the pleural cavities of 36 2-month-old Sprague-Dawley rats.
Two control groups, untreated and saline-injected, were utilized.
Necropsy was performed after the rats died or killed when moribund. No mesothelial neoplasms were found in either controls
or in rats treated with Attapulgite. Survival times between the
Attapulgite-treated group and the controls were not statisticallydifferent.
Wagner, Griffiths, and Munday (1987) injected 20 male and
20 female, SPF Fischer rats intrapleurally with single injectionsof Attapulgite. Three samples of Attapulgite named after thelocation of their discovery (Lebrija, Torrejon, and Leichester)
were utilized in this study. No concentrations were provided.

TABLE 14
Tumors in rats treated with intrapleural injections of four Aluminum Silicate samples (Pigott and Ishmael 1992)
Tumor

Control

Chry. Asbestos

SaffilSaffil aged

Alumosil. A

Alumosil. B

Total no. of animals
No. of benign
No. of malignant
Malignant mesothelioma

62
44
17
0

81
55
26
7

71
57
16
0

68
56
14
0

57
46
10
0

67
49
19
3

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SILICATESTABLE 15
Toxic reactions to intrapleural injections of Attapulgite(Wagner, Griffiths, and Munday 1987)
Dust

Mesothelioma

Nonmesothelioma

Lebrija Attapulgite
Torrejon Attapulgite
Leichester Attapulgite
Crocidolite
KaolinSaline

2
14
30
34
0
1

38
26
2
6
40
39

However, fiber length information was provided. Lebija Attapulgite had fiber lengths of ≤2 µm. Torrejon Attapulgite contained at the most 0.54% of fibers ≥6 µm. Leichester Attapulgite
contained about 19% of fibers ≥6 µm. The animals were allowed
to live their life span but were killed if they appeared distressed.
Upon death, necropsy and microscopic examination of tissue
were performed. Dust extraction was obtained from granulomas removed from the diaphragm or mediastinal tissue. Twocontrols were used in this experiment; Kaolin and saline. One
positive-control crocidolite was also used. The results from thisexperiment are summarized in Table 15.
Lebrija Attapulgite dust extracted from the lung had fibers≤2 µm. Material examined from Torrejon Attapulgite was fibrous and have fiber length up to 8 µm. Leichester Attapulgite
fibers from extracted lungs were up to 25 µm. The investigators
considered these fibers to be tumorigenic. Kaolin was a nonfibrous dust and crocidolite was fibrous. The authors concluded
that exposure to Torrejon, and Leichester Attapulgite should be
avoided (Wagner, Griffiths, and Munday 1987).
Lemaire et al. (1989) reported a study in which groups of fiverats received single intratracheal instillations of Attapulgite at 1,
5, and 10 mg. One month after treatment, BAL and microscopic
examination of the lungs were performed. The average lengthof the fibers were 0.8 µm and 100% of the fibers were less than
3 µm. Every test animal had type A lesions. Type A lesions arecharacterized by an accumulation of inflammatory cells mostly
macrophages, and epithelioid cells around fiber deposits. These
inflammatory cells form a compact cellular infiltrate at the periphery of the deposits and some are focally dispersed throughout the alveolar region. The BAL had mostly macrophages and asmall number of neutrophils at 5- and 10-mg doses. At the 5-mg
dose, 3.6% of the cells were lymphocytes.
In a study by Renier et al. (1989), intrapleural injections of
20 mg of different Attapulgite fiber samples in 1 ml of saline
were given to 2-month-old Sprague-Dawley rats. The control
group received only a saline injection. All rats were allowed
to live full life span. The mean length of Attapulgite fibers inthis experiment was 0.77 µm. The number of groups were notreported; however, 36 rats were reported to comprise each group.
Pulmonary and thoracic neoplasms were fixed and processed forhistopathological examination. The survival time of the treated77

groups (788 ± 155 days) was very similar to that of the control
groups (809 ± 110 days). The incidence of mesothelioma was
0% for control groups and treated groups. Attapulgite in thepresent experiment was not carcinogenic (Renier et al. 1989).
Lemaire (1991) reported a study in which groups of five animals received doses of 1, 5, or 10 mg of Attapulgite by transtracheal injection to examine alveolar macrophage (AM) production of interleukin-1 (IL-1) and macrophages-derived growth
factor (MDGF) from fibroblasts. Saline and UICC chrysotile B
asbestos were used as controls. At 1 month, Attapulgite produced granulomas and the UICC chrysotile B produced fibrosis.
At 8 months, the granulomatous reactions had either resolved
or were greatly diminished, whereas the fibrosis persisted. Cells
obtained by BAL included multinucleated giant macrophages inanimals treated with Attapulgite, but not in those treated with
UICC chrysotile B. Enhanced production of IL-1 was seen in
all treated groups. MDGF production was only seen in animals
with lung fibrosis.
Coffin, Cook, and Creason (1992) injected a single dose of
0.5, 2, 4, 8, 16, or 32 mg of Attapulgite intrapleurally into six
groups of 25 Fischer 344 rats. Nearly all the fibers were <1 µm
in length. Mesotheliomas were present in 2/140 treated rats compared to 1/79 incidences in control groups. The median life span
was 839 days for Attapulgite-treated animals and 729 days for
nontreated animals.
Bentonite
Sykes et al. (1982) investigated the effects of Bentonite dust
administered by intratracheal instillation in rats. A 0.5-mg doseof Bentonite with a mean size of 0.3 µm was instilled intratracheally. Control animals were injected with sterile saline andTiO2 (a nontoxic dust). Animals were killed at 1, 2, 6, 24, and48 h; and 4 and 7 days after instillation. Bronchopulmonary
lavage (BPL) was carried out and AMs and polymorphonuclear(PMN) leukocytes were recovered. The activity of LDH andprotein content of the lavage fluid were also determined. In asecond experiment, after instillation of 5 mg of Bentonite, theanimals were killed at 1, 7, 49, and 100 days. In addition to theabove, peroxidase and lysozyme activity were measured.
In the first experiment, a rapid influx of PMN leukocytes was
detected at 6 h. PMN leukocyte response peaked at ∼19 × 106
cells after instillation and started declining more slowly up to
4 days. At 7 days, the PMN leukocyte numbers were 2.5 × 106 .
The greatest increase in the numbers of AMs recovered occurredat 4 and 7 days. The mean diameter of macrophages increased
from 11.0 to 12.5 µm over the first 48 h after instillation. The
mean diameter decreased at 4 and 7 days. LDH activity at 24 h
was maintained at 40 mU cm−3 and then increased (73 mU cm−3 )with the influx of PMN leukocytes into the lungs after 48 h.
Protein concentration was calculated at 500 µg cm−3 for the
first 24 h and was maintained for 48 h.
In the second experiment, large number of PMN leukocytes
were recovered at day 1. However the severity of the response
did not differ significantly from the 0.5 mg dose. By 7 days,

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78

COSMETIC INGREDIENT REVIEW

the numbers had decreased and was similar to control values. A
significant decrease in the number of AMs compared to controls
was observed at 24 h after instillation. This decrease was followed by a sharp increase that exceeded control values by 7 days.
Total number estimates were similar to those of the first experiment. LDH activity and protein concentration from Bentonite
and TiO2 were very similar. The initial rise at day 1 following
administration was short-lived. Peroxidase activity was minimal. Lysozyme activity rose sharply between 1 and 7 days, but
returned to control values at 49 and 100 days (Sykes et al. 1982).
Marek and Blaha (1985) gave subplantar injections of 0.05 mlof a 5% solution of Bentonite to male Wistar rats. The rats either received both hind paw injections at an interval of 24 hor their left paw was injected with Bentonite and their rightpaw injected with 0.05 ml of a 10% solution of Kaolin. The
injection was of Kaolin. Subcutaneous Bentonite granulomas
were produced on the left side, both dorsally and ventrally. Simultaneously Kaolin granulomas were produced on the rightside analogous to the Bentonite injection. Sodium salicylate andprednisone suppressed the Bentonite edema during the first 24 h.
The presence of mononuclear cells was confirmed.
Tatrai et al. (1983) administered a single dose of 40 mg of
Bentonite suspended in 1 ml of physiological saline containing
40,000 IU of crystalline penicillin intratracheally to male CFY
rats. The Bentonite’s composition consisted of 73% Montmorillonite, 18% cristobalite, 3% quartz, 3% feldspar, and 3% otherminerals. Particle sizes were <2 µm. The control group received
1 ml of physiological saline containing 40,000 IU of crystalline
penicillin. Animals were killed 12, 24, 48, or 72 h or 90 days after
exposure. Body and lung weight of the rats were measured. The
right lung was fixed and sectioned for microscopic examination.
The lipids and phospholipids were analyzed in the left lung.
The body weights of the rats were moderately decreased andthe lung weight increased 72 h after Bentonite exposure. After 90 days, the lung weight was only slightly greater than thatof the control animals. Upon microscopic examination at 12 h,
Bentonite exposure had resulted in a nonspecific inflammationof mostly neutrophils with perivascular edema, alveolitis, andincipient bronchopneumonia. A small number of macrophages
and lymphocytes were detected. Dust particles were observed in
the leukocytes and macrophages or extracellularly in the alveoli.
After the 24th h, bronchopneumonia was present after coalescence of the inflammatory foci; the pneumonia then became
necrotizing and desquamative. Necrotic neutrophilic leukocytes
and eosinophil leukocytes were observed. The reticular network
collapsed between the 48th and 72nd h. Exposure after 90 days,
included dust storage foci filled with large foamy cells with palecytoplasm. Closely packed cells with dark cytoplasm and nuclei
were located at the periphery.
After 12 and 24 h, the amount of lipids and phospholipids
in the lungs was not altered. However, between 48 and 72 h,
the lipid and phospholipid content increase but distribution remained the same. After 90 days, the value was the same as seen
at 72 h. (Tatrai et al. 1983).

Hatch et al. (1985) assessed the ability of Bentonite to increase susceptibility to bacterial pneumonia. Bentonite was injected intratracheally into mice at concentrations of 1, 10, and100 µg. In vivo bacterial-infectivity screening assays were conducted by exposing the animals to aerosolized Group C Streptococcus species. The severity of infection was calculated byrecording the deaths of the mice over a 15-day period. Control
animals were exposed to TiO2 , a nontoxic dust. At the 100-µg
dose, Bentonite increased the infectivity of the bacteria. Mortality was 85%. Even at 10 µg, Bentonite caused increased animal
mortality (43.3%). Control dusts at 100 µg produced only a 5%mortality (Hatch et al. 1985).
In a study by Tatrai et al. (1985), male CFY rats were givena single dose of 60 mg of Bentonite, in 1 ml of physiologicalsaline containing 40,000 IU crystalline penicillin, by the intratracheal route. Bentonite particle size was less than 5 µm.
Control groups received 1 ml physiological saline containing
40,000 IU penicillin. Animals were killed at the end of 72 h, the
2nd and 4th week, and the 3rd, 6th, and 12th month. The acidphosphatase activity and the progression of fibrosis was determined. The lungs were processed for microscopic examinationand fibrosis determined by Belt and King’s classification. The
results from this experiment are presented in Table 16. Acid
phosphatase activity was increased at 72 h and had returned tonormal by the first month.
Bentonite dust was administered intratracheally as a single 60-mg dose to Sprague-Dawley rats in a study by Adamis
et al. (1986). The animals were killed 3, 6, and 12 months after exposure. The right lung was studied microscopically andthe lipids, phospholipids, and hydroxyproline were determined.
Significantly greater phospholipid values compared to controls
were observed. Among the phospholipid fractions, the greatest quantitative increase was seen in phosphatidylcholine (morethan twice the control) and the smallest increase was seen inphosphatidylethanolamine (less than 1.6 times). After 6 and12 months, the values were similar. Lung lipids had a greater
range of values than did the phospholipids (no details given).
The wet weight of the lung in grams increased in 5% to 10%
Bentonite-treated rats compared to controls at month 3. No

TABLE 16
Toxic effect of intratracheal instillation of Bentonite(Tatrai et al. 1985)
Time after instillation
End point

72 hours

1st month

12th month

Acid phosphataseactivity
Fibrosis

72

—

—

N/A

Loose reticulin Loose reticulin
fibrils, nofibrils, nocollagencollagenDistributed for Comment Only -- Do Not Cite or Quote
SILICATES

difference was detected at 6 and 12 months. Hydroxyproline
content of treated rats (mg/g lung wet weight) was very similar
to controls at 3, 6, and 12 months (Adamis et al. 1986).
Calcium Silicate
Bolton et al. (1986) injected three Calcium Silicate samples
into the peritoneal cavity of three groups of 36 rats. Each rat
was given a single injection of 25 mg of dust and allowed tolive out their life span. At necropsy, little dust or dust-related
fibrosis was visible in the peritoneal cavity. No mesotheliomas
developed in any of the animals.
Richards, Tetley, and Hunt (1981) compared the biological reactivity of three samples of Calcium Silicate (A, B, and C) in vivo
to that of chrysotile and titanium dioxide. Titanium dioxide andsaline were considered negative controls, while chrysotile wasconsidered a positive control. Groups of 32 female, MRC hooded
rats were instilled intratracheally with 0.25, 0.50, 1.0, or 5.0 mg
of Calcium Silicate. At weeks 1 and 4 after instillation, the control and treated rats were killed. The lungs were lavaged and thereactivity of the minerals to free cell populations, lavaged lungtissue, and pulmonary surfactant was conducted. All mineraldoses of 5 mg induced an increase in the number of free cells
at week 1. Only sample B increased in cell numbers at lower
doses. At the end of 1 week, sample B was considered morereactive than either sample A or C, but chrysotile was considered more reactive than sample B. At 4 weeks, the effects seenfrom samples A and B are almost completely reversed and werecomparable to that of titanium dioxide. Sample B at 4 weeks produced a greater or a comparable activity to chrysotile. No mineralogical analysis of the Calcium Silicate samples was provided.
KaolinZaidi et al. (1981) investigated the effect of Candida albicans in modifying the fibrogenisis caused by Kaolin. Fivegroups of guinea pigs were injected intratracheally with C. albicans (500 µg); Talc dust (75 mg); Talc and C. albicans; Kaolin(75 mg); or Kaolin and C. albicans. Two animals from eachgroup were killed at 1, 7, 15, 30, 60, 90, 120, and 180 days after injection. The lungs were collected for bacteriological andmicroscopic examination. The combined effect of Kaolin andthe organism incited an acute inflammatory reaction similar to
Kaolin dust alone at day 1. However, Kaolin and the organism
produced thick reticulin and collagenous fibrosis, unlike Kaolin
alone. Talc produced only a thin reticulin fibrosis not enhancedby the presence of the organism. The enhanced fibrogenicity was
attributed to the adjuvant activity of Kaolin with the polysaccharide glucan component of C. albicans.
Edwards et al. (1984) gave 12 fetal lambs and six fetal monkeys subarachnoid injections of Kaolin. A sterile suspension
of 2% Kaolin in saline was injected into the cisterna magna.
Fetal lambs received 1 to 3 ml of Kaolin and fetal rhesus monkeys received 0.5 to 1.0 ml. After injection the fetuses were replaced into the uterus. Prenatal ultrasound monitoring was used
to document the progression of fetal ventriculomegaly. Cesarean

79

sections were scheduled for 140 to 145 days for the sheep and
160 to 165 days for monkeys. Newborn animals with gross headenlargement were killed 2 h after birth and necropsy was performed. Brains were sectioned for gross and microscopic examination. Five lambs and one monkey underwent ventriculoamniotic shunting at 120 days after gestation.
Ventricular dilatation was apparent at 1 week following
Kaolin injections. The cerebral mantle was markedly thinned,
with relative preservation of the cortex and severe attenuationof the white matter. The average cortical thickness of the cingulate gyrus in the Kaolin-injected sheep was 716 µ compared to1225 µ in control animals. The corpus callosum was an averageof 125 µ in thickness in the sheep compared to 475 µ in control
animals. Microscopic examination of the cortical neurons were
well preserved and contained the complexity and density of neural processes. A mild-to-moderate fibrotic reaction and inflammatory cell response along the basal meninges was apparent. A
large number of macrophages containing Kaolin infiltrated thesubarachnoid space. In five fetuses, Kaolin was injected mistakenly into either the epidural tissues superficial to the cisterna
magna or into the cervical musculature. None of these fetuses
had hydrocephalus at birth (Edwards et al. 1984).
Hatch et al. (1985) assessed the ability of Kaolin to increase
susceptibility to bacterial pneumonia. Kaolin was injected intratracheally into mice at a dose of 100 µg. In vivo bacterialinfectivity screening assays were conducted by exposing the animals to aerosolized Group C Streptococcus species. The severityof infection was calculated by recording the deaths of the miceover a 15-day period. Control animals were exposed to TiO2 , anontoxic dust. A 100-µg dose of Kaolin caused statistically significant but modest (<50%) increased death due to infection bya large dose. Mortality was calculated at 38.9%. Control dusts
at 100 µg produced only a 5% increase in mortality.
Wagner, Griffiths, and Munday (1987) used Kaolin as a negative control in a previous intrapleural injection study. The protocol and results are cited under Attapulgite in this section.
Fugiyoshi, Hayashi, and Oh-ishi (1989) reported a study inwhich Kaolin, a known activator of factor XII, was injected intraperitoneally into mice at 2.5 mg/mouse to study the Kaolininduced writhing response. The writhing responses were observed in the 10 min after treatment and the mean number of
responses was 9.2. Sixty minutes after the Kaolin injection, captopril (20 µg/mouse) was injected and the writhing response wasobserved again for 10 min after injection. Captopril is an antihypertensive and vasodilator. A second study was conducted byadministering bromelain (10 mg/kg intravenously) followed by
the injection of Kaolin 30 min later. Bromelain is a standardized complex of proteases from the pineapple plant purported tohave primarily antiedema, antiinflammatory, and coagulationinhibiting effects. The response was not reproduced.
Montmorillonite
Heat-treated Montmorillonite in doses of 5, 15, and 45 mg was
given to groups of four Sprague-Dawley rats by intratracheal

Distributed for Comment Only -- Do Not Cite or Quote

80

COSMETIC INGREDIENT REVIEW

instillation. Following a 3-month postexposure period, the animals were killed and tissues were subjected to microscopic
examination. The Montmorillonite particles were mainly restricted to alveoli within and adjacent to alveolar ducts regardlessof dose. Most particles were contained within small to moderate numbers of pulmonary AMs. However, some particles were
free in alveoli. Adjacent alveoli septae were mildly thickened.
Interstitial fibrosis was present in all groups. At the 5- and15-mg doses, fibrosis was mild to moderate, multifocal, andloose, meaning less collagen. The 45-mg dose produced dense
fibrosis. Macrophages contained clay particles and lymphocytes
were present in the lesions. Occasionally giant multinucleate
cells were seen (Schreider, Culbertson, and Raabe 1985).
ZeoliteA single intratracheal administration of 50 mg of Zeolite dust
was given to male rats and observations were made at 1 and
3 days, and 1 and 3 months after injection. Time-dependent increases in phagocytosis were observed. Morphological changes
in the lungs was described as exogenous fibrous alveolitis(Kruglikov, Velichkovsky, and Garmash 1990).
Zeolite (Clinoptilolite)
Kruglikov et al. (1992) reported a study in which a single
intratracheal instillation of 50 mg of Clinoptilolite was made tomale rats. On days 1, 3 to 5, and 18 after injection, lung tissues were examined histopathologically. On the first day, thesmallest Zeolite particles were phagocytized by neutrophils,
whereas larger particles were phagocytized by macrophages.
About a fourth of macrophages had phagocytized more than six
dust particles per cell and <2% of macrophages were degenerated. At 3 to 5 days, no more particles were seen in neutrophils
and their numbers had decreased. However, the percentage ofmacrophages containing more than six dust particles in the cytoplasm increased to 90%. Only 7% of macrophages degenerated.
On day 18, the pattern of phagocytosis was similar to that at days
3 to 5, but 4% of macrophages were degenerated.
Tatrai and Ungv’ary (1993) instilled single intratracheal dosesof 30 and 60 mg of Clinoptilolite particles to groups of 50 maleand female (equal numbers) Wistar rats. The particles were
<5 µm and were suspended in 40,000 IU crystalline penicillin.
Controls received only saline instillations. All survivors were
killed at the end of the study. Examination for gross and microscopic lesions were conducted. None of the treated groups hada significant increase in the incidence of any specific neoplasms
compared to the controls. No positive trend was noted in theoccurrence of neoplasms. Neoplasms seen within both control
and treated animals were similar in the anatomical sites in which
they were found and their histological feature.
Zeolite (Mordenite)
Suzuki (1982) gave two groups, one of 18 and one of 5 male
Swiss albino mice, a single injection of 10 or 30 mg Zeolite intraperitoneally. The control animals were untreated. Tenmonths after exposure, no neoplastic changes were observed in
the treated animals. Nearly all (98%) of the sample particles
were <5 µm.
Suzuki and Kohyama (1984) administered a single injection of 10 mg of Mordenite to a group of 50 male BALB/cmice. The control animals received saline injections. The Mordenite sample was comprised of 94% of particles <3 µm. No
peritoneal tumors were observed in any of the control animals.
Mild peritoneal fibrosis was seen in treated mice, but no peritoneal or any other organ neoplasms were observed between 7 to
23 months.
Tatrai, Wojn’arovits, and Ungv’ary (1991) made intratracheal
instillations of 60 mg of Mordenite to groups of 10 rats. The animals were killed at 1 week, and 1, 3, 6, and 12 months after
exposure. Lesions in the lungs were observed. Nonspecific confluent bronchopneumonia was observed at 1 week after exposureand sequestration of macrophages at 1 month after exposure.
Mild fibrosis was observed at later times. After 12 months, thealuminum:silicon ratio in macrophages was similar to the ratio
in natural Zeolites.
Tatrai et al. (1992) reported the changes in cervical and hilar
lymph nodes in the test animals treated in the above study as seen
by electron microscopy and light microscopy. By the end of thefirst year, dust storing macrophage foci developed in the lymph
nodes with minimal fibrosis. Also 3/10 of the rats had atypical hyperplasia. Electron microscopy showed the dust stored inmacrophages without structural changes. However, dispersive
x-ray microanalysis of the intracellularly stored dust revealed theratio of the two main elements, aluminum and silicon, changed
with respect to aluminum as compared to the original Zeolite
sample.
Zeolite (Nonfibrous Japanese Zeolite)
A single intrapleural injection of 20 mg of Nonfibrous
Japanese Zeolite was administered to two groups of 20 male and
20 female Fischer 344 rats. Control rats received saline injections alone. Mean survival time for control animals was 720 days
and 715 days for treated animals. One pleural mesothelioma wasfound in the control group and one pleural and one peritoneal
mesothelioma was found in the treated group (Wagner et al.
1985).
Zeolite (Synthetic Zeolite 4A)
A single intraperitoneal injection of 10 mg of Synthetic Zeolite 4A was given to groups of 50 male BALB/c mice. The
average particle length of the sample was 2.24 µm. Treated animals were observed for 7 to 23 months after exposure and nomesothelioma were observed (Suzuki and Kohyama 1984).
Zeolite (Synthetic Zeolite MS4A and MS5A)
Maltoni and Minardi (1988) reported a study in which groupsof 20 male and 20 female Sprague-Dawley rats received a single
intraperitoneal injection of 25 mg of Zeolite MS4A (sodium aluminum silicate) or MS5A (calcium aluminum silicate) or water

Distributed for Comment Only -- Do Not Cite or Quote81

SILICATES

only (control). Observations were made for the animal’s entire
life span and microscopic examination was performed. One peritoneal mesothelioma in an Zeolite MS4A-exposed rat was foundat 141 weeks after treatment.
These same authors administered single intrapleural injections and single subcutaneous injections of 25 mg of Zeolite
MS4A and MS5A or water to separate groups of 20 male and
20 female Sprague-Dawley rats. No difference in incidences oftumors was found among control and treated animals (Maltoni
and Minardi 1988).
Zirconium Silicate
In a study by Harding (1948), a 3-ml dose of a 10% suspensionof Zircon in milk and saline was injected intraperitoneally into
three cavies (guinea piglike rodent). The animals were killed
nearly a year later. At microscopic examination, a dry opaquematerial was embedded in the peritoneum of the abdominal wall
over the small intestine, and in the omentum. Growth was notaffected.
The accumulation of Zirconium Silicate in tissue was reported by Stookey et al. (1967). In one study, six young adultmale rats were anesthetized and were given subcutaneous injections into their back. Half of the rats were injected with saline
to serve as controls and the other half were injected with 0.3 mlof an aqueous 50% slurry of Zirconium Silicate. Three weeks
after the injections, the animals were killed. Tissue surrounding the injection site was excised and prepared for microscopic
examination. Zirconium Silicate deposits were observed as discrete nodules with a narrow surrounding connective tissue wallin the deep connective tissues of the back. Saline controls had
no lesions and in some cases, healing was complete.
In another study in this report, eight young adult female rats
were divided into four equal groups according to body weight
and their tissues were subjected to microscopic examination
following saline and Zirconium Silicate or sodium zirconium

lactate injections. Group 1, the control group, was given a single
injection of 0.05 ml of isotonic saline in four different areas:
subcutaneous injections in the right buccal mandibular mucosa;
periosteal injections in the left buccal mandibular periosteum;
intramuscular injections on the ventral side of the left thigh; subcutaneous injections in a shaved area on the back located about
1 inch behind the shoulders of the midline. Group 2 was similarly injected with 0.05 ml of a 20% slurry of Zirconium Silicate.
Groups 3 and 4 were injected with 0.05 ml of a 20% solution of
sodium zirconium lactate and a 20% slurry of flour of pumice.
All animals were killed 1 week after the injections and tissue
samples for histological sections were taken at each injection
site. An identical study with the same experimental proceduresas the above study used adult male guinea pigs. In each species,
saline injections produced no effect, Zirconium Silicate caused
minimal toxicity, and sodium zirconium lactate plus pumice was
toxic. The results from these two studies are listed in Table 17.
The results pertain to both the rat and guinea pig studies. Zirconium Silicate deposits were described as well circumscribedmasses of particulate material surrounded by a narrow zoneof new connective tissue. Nonspecific muscle damage, without
necrosis due to the presence of the particulate matter and the volume of injected material, was localized to the immediate vicinity of the injection site. Macrophages along a border of a massof Zirconium Silicate had reflective material within their cytoplasm. Dispersed particles were phagocytized by macrophages,
with little or no associated inflammatory response. No evidenceof bone resorption was found adjacent to periosteal deposits.
In another study by these authors, skin and muscle tissue samples were taken for microscopic examination. Eight adult rats
were anesthetized and a deep incision was made on the ventral
side of the left rear leg. The incision was made in the quadratus
femoris muscle. The animals were exposed to 50 mg of pumiceflour, silica dioxide, and Zirconium Silicate, respectively. Insertion of the appropriate substance was made into the muscle

TABLE 17
Toxic reactions to injected Zirconium Silicate (Stookey et al. 1967)
Degree∗ of tissue reaction
Animalspecies

Agent injected

Rat
Rat
Rat
Guinea pig
Guinea pig
Guinea pig

SalineZirconium Silicate
Sodium zirconium lactate and pumice
SalineZirconium Silicate
Sodium zirconium lactate and pumice∗
0 = reaction absent.
+ = mild inflammatory reaction of little consequence.
++ = mild reaction with granulomatous response.
+++ = destructive granulomatous reaction.

Concentration(%)
20
45 and 2020
45 and 20

Oral
mucosaSubcutaneous
tissues

Periosteal
tissueIntramuscular
tissue

0
+
+++
0
+
+++

0
+
+++
0
+
+++

0
0
+++
0
+
+++

0
+
+++
0
+
+++

Distributed for Comment Only -- Do Not Cite or Quote

82

COSMETIC INGREDIENT REVIEWTABLE 18
Toxic reactions to implantation of Zirconium Silicate
in muscle tissue (Stookey et al. 1967)of each of the samples Morimoiron, Georgia, and Lebrija. The<50% fiber length was 0.7, 0.5, and 0.8 µm, respectively, and a<50% fiber diameter of 0.07, 0.07, and 0.04 µm, respectively.
Some rats died spontaneously or others in poor health were
killed. Surviving animals were killed 2.5 years after treatment
for necropsy. At necropsy, neoplasms or organs with suspected
neoplasm tissue were fixed for microscopic examination. These
three samples were noncarcinogenic. The results are presented inTable 19.
In another experiment by the same investigators, a fourthsample of Attapulgite from Caceres was tested. Intraperitoneal
injections of 2, 4, and 4 mg were administered consecutively
for 3 weeks. The fiber length and diameter of this sample were<50% 1.3 and 0.07 µm, respectively. Animals in poor healthwere killed. Surviving animals were killed 2.5 years after treatment for necropsy. At postmortem examination, parts of neoplasms or organs with suspected neoplasm tissue were fixed for
microscopic examination. The results were considered moderate
in relation to the dose. The Caceres Attapulgite sample results
are also presented in Table 19 (Pott et al. 1987).

Degree of tissue reaction∗
Agent embedded
in muscle

Amount(mg)

Subcutaneous
tissueIntramuscular
tissuePumiceSilica dioxide
Zirconium Silicate
Control

50.0
50.0
50.0

+
++
+
0

+
+++
+
0

∗

0 = reaction absent.
+ = mild inflammatory reaction of little consequence.
++ = mild reaction with granulomatous response.
+++ = destructive granulomatous reaction.

incision and into the skin 1 cm lateral to the muscle incision.
Control animals had the same muscle incision, but no foreignmaterial was inserted. One animal from each group was sacrificed 10 days following surgery. The remaining animals weresacrificed 30 days from the incision. All tissue was fixed andprepared for microscopic examination. Table 18 presents thedata from this experiment.
Adjacent tissues were free of inflammation or evidence of
injury at 10 and 30 days. Deposits of Zirconium Silicate wereidentified and were surrounded by a narrow zone of new connective tissue. No necrosis was identified (Stookey et al. 1967).

KaolinToxicity of some of the minerals present in coal-mine dust
was examined by Martin, Daniel, and Le Bouffant (1975). Fivehundred female SPF Sprague-Dawley rats were divided into
groups each with 10 animals. The rats were exposed over a
period of 3 months to 50-mg/rat intratracheal instillations of
Kaolin. The following assessments were made: weight of the
fresh lungs; macroscopic and microscopic lesions in the lungs;
amount of collagen and dust present in the lungs; and calculation of the toxicity index from the amount of collagen formed
per mg of dust. The weight of fresh lungs subjected to Kaolin
was 1.76 g. Collagen formed per lung was 23.9 mg. The dust
per lung was 30.2 mg and the collagen/dust ratio was 0.79. Microscopic examinations of the lungs showed no alveolar proteinosis but Kaolin was detected in the bronchiolovascular lymphoid sheaths. No information regarding nonexposed lungs waspresented. The opinion of the investigators was that exposure to

Short-Term Parenteral
Attapulgite
Pott et al. (1987) conducted a study in which three samples of Attapulgite labeled Georgia, Lebrija, and Morimoiron
were injected intraperitoneally to study their carcinogenic effects in rats. Each sample was injected one time each week for
9 weeks at 60 mg per injection. The number of female Wistar
rats for each of the samples (Georgia, Lebrija, and Morimoiron)was 112, 115, and 114, respectively. Fiber analysis was madeTABLE 19
Carcinogenic effect of intraperitoneal injection of Attapulgite from four sources (Pott et al. 1987)
Lifespan (weeks) after treatment of
All rats
Attapulgite No. of % of rats
sample source rats with tumors
MormoironLebrija
Georgia
Caceres

114
115
112
30

3.5
3.5
3.6
40.0

Rat with tumors

Time to death Time to death Time to death All rats Time to death Average timefor <20%for <50%for <80% of dead byof first rat
to death of ratsof all ratsof all rats
all rats
this time with tumor
with tumors
92
95
89
94

116
116
108
109

138
134
129
132

164
164
163
142

47
98
75
74

92
114
100
116

Distributed for Comment Only -- Do Not Cite or Quote
SILICATES

Kaolin results in “pulmonary toxicity” and possesses “fibrogenic
capacity” (Martin, Daniel, and Le Bouffant 1975).
Magnesium Silicate
An emulsion of Magnesium Silicate, 500 mg in 1 ml of saline,
was injected subcutaneously into groups of 10 female Wistar rats
once daily at 2, 4, 6, 13, or 20 days. As controls, 12 nontreatment rats were killed on the first experimental day and 12 rats
were injected with 1 ml of saline once daily for 20 days. The
trabecular bone, sinusoids, and hematopoietic cells were processed for microscopic examination. No significant change inthe volume percentage of hematopoietic cells, sinusoids, or trabecular bone was present in the day-2 treatment group. After
4 days of treatment, the volume percentage of hematopoietic
cells increased rapidly, sinusoids decreased rapidly, and trabecular bone decreased gradually. The volume percentage ofhematopoietic cells was about 2.6 times normal, and that ofsinusoids and trabecular bone was about 30% and 60% of normal, respectively, after 20 days of treatment. The tibia metaphyses had the following changes after 4, 6, 13, and 20 daysof treatment; sinusoids were compressed by the markedly proliferated myelocytic element and severely narrowed the distance
between the sinusoidal wall and the surface of trabecular bone
was markedly increased. Atrophy of the thin trabecularbone was seen but no significant changes in osteocytes, osteoblasts, or osteoclasts were seen (Shibayama, Nishioto, andNakata 1993).
Zeolite (Clinoptilolite)
Three intrapleural injections of 20 mg of Clinoptilolite were
given in monthly increments to a group of 44 male and 49
female rats. Control animals received only saline injections.
The Zeolite sample was described as having the formula:(Na,K) Ca[Al6 Si30 O72 ] · 20H2 O, with Cu, Pb, Zn, Ni, Co, Mo,
Mn, Ti, Sr, Ba, and Hg contamination. Particle size measurements were recorded as follows: <3 µm, 6.5%; 5 µm, 5.9%;
10 µm, 5.9%; 10–30 µm, 20.6%; 30–100 µm, 35.1%; 100–
500 µm, 26.1%. Pulmonary lymphosarcomas, pleural and abdominal lymphosarcomas, and lymphatic leukemias were observed in 47/93 treated animals and 5/45 saline-treated animals.
No mesothelioma or pulmonary neoplasms were observed in
the controls. Mesothelioma and bronchial carcinoma were detected in 2/93 and 1/93 treated animals, respectively (Pylev et al.
1986).
Zeolite (Phillipsite)
Three intrapleural injections of 20 mg of Phillipsite given inmonthly increments were administered to a group of 44 maleand 49 female rats. Control animals received only saline injections. The Zeolite sample was described as having the formula: (Na1.38 K0.53 Ca0.87 Mg0.25 )(Si11.93 Al4.03 O32 ) · 9H2 O. Particle size measurements were recorded as follows: <5 µm, 14.5%;
10–30 µm, 32.8%; 50–70 µm, 16%; ≥100 µm, 36.7%. Neoplasms were found in 41/101 Zeolite-treated rats (50 tumors).

83

Tumor types included 1 pleural mesothelioma, 2 pulmonary adenocarcinoma, 29 hemoblastosis, 7 mammary gland neoplasms,
and 11 neoplasms found at other sites. In control animals, 16
neoplasms (pulmonary, pleural, and abdominal lymphosarcomas, lymphocytic leukemias, and mammary gland neoplasms)
were identified in 14/52 rats (Pylev et al. 1986).
Zirconium Silicate
Harding (1948) reported results when an adult rabbit received
intravenously four doses over 1 week of a 5-ml suspension of a
10% solution of Zircon. The animal was killed 33 weeks later.
At microscopic examination revealed small clumps of crystals
were close to the portal tracts of the liver. The clumps were in
the Kupfer cells. Fibrosis was detected. Small clumps of crystals
were also observed in the spleen and alveolar walls and spacesof the lungs.
In another study in this report, six young rats were injected
intratracheally with 1 ml of a 10% solution of Zircon. Three rats
were killed after 7 and 9 months. The lungs were radiographedand sectioned for microscopic examination. Much of the material was found free within the alveoli and lymph vessels of
the lungs. A small amount was found within phagocytic cells.
Swollen histiocytes were seen in a few alveoli. Fibrosis was notevident (Harding 1948).
Inhalation
Attapulgite
Wagner, Griffiths, and Munday (1987) exposed 40 (20 maleand 20 female) SPF Fischer rats to Attapulgite dust in an inhalation chamber. The rats were exposed to two samples of Attapulgite (named by the region in which they were mined, Lebrija
and Leichester) at a concentration of 10 mg/m3 for 6 h/day for
5 day/week until they were killed. At 3, 6, and 12 months, fouranimals were killed. All remaining rats were allowed to live
their life span. All animals were subject to necropsy; the lungs,
liver, spleen, kidneys, and other relevant organs were examined
microscopically. Mineralogical analysis, examination of ashedlung sections and examination of macerated lung tissue, werealso performed. Kaolin, the negative-control dust, and Chrocidolite UICC, the positive-control dust, were also administered
at a dose of 10 mg/m3 .
At microscopic examination, one peritoneal mesothelioma,
one adenocarcinoma, and three bronchoalveolar hyperplasia
were found in rats treated with Lebrija Attapulgite. Thirty-fiverats had no proliferative changes. In rats treated with Leichester Attapulgite, proliferative lesions observed included two
mesothelioma, one peritoneal mesothelioma, one malignant
alveolar neoplasm, two benign alveolar neoplasms, and eightbronchoalveolar hyperplasias. Twenty-seven rats had no proliferative lesions. Rats exposed to the negative-control Kaolin had
two bronchoalveolar tumors. Rats in the positive-control Crocidolite group had one adenocarcinoma and three bronchoalveolar
tumors. The mean fibrosis grades of each treatment group arepresented in Table 20.

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84

COSMETIC INGREDIENT REVIEWTABLE 20
Toxicity of inhaled Attapulgite dust (Wagner, Griffiths, and Munday 1987)

Dust source

Total no.
of rats

Lebrija Attapulgite
Leichester Attapulgite
KaolinCrocidolite UICC

40
40
40
40

Mean fibrosis grade as function of time after exposure
3 months

6 months

12 months

24 months

3.1
3.0
2.8
4.1

2.6
3.1
2.75
3.3

3.2
4.0
2.4
3.1

3.2
—
2.1
3.8

The classification of proliferative lesions and neoplasms corresponding to the mean fibrosis grades are as follows: (1) bronchoalveolar hyperplasia—no malignant proliferation of the epithelia; (2) benign alveolar neoplasm; (3) malignant alveolar
neoplasm; (4) adenocarcinoma; (5) squamous carcinoma;(6) adenosquamous carcinoma; and (7) mesothelioma.
The Lebrija Attapulgite dust extracted from the animal lungs
did not have short fibers and the presence of granular material
and long fibers. The Leichester Attapulgite dust also had thepresence of long fibers. Kaolin is a nonfibrous dust. UICC Crocidolite is a fibrous dust but lengths were not published in thisstudy (Wagner, Griffiths, and Munday 1987).
Calcium Silicate
Bolton et al. (1986) exposed white male Wistar rats to cloudsof 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. A total of four inhalation chambers
were used with 48 animals/chamber. One chamber was reserved
for control animals receiving only filtered air. The remaining
three chambers were used to test three samples (A, B, and C)
of Calcium Silicate. Twelve rats were killed from each of thechambers at the end of the dusting period. The final surviving
animals were killed at the end of 19 months after exposure.
At necropsy, tissue samples and one lung were taken from all
major organs for microscopic examination. The other lung was
taken for lung-dust analysis. The lung was dried and prepared
for infrared analysis. Blood samples were taken 5 days prior to
the start of the exposure and 3 days after the exposure.
All Calcium Silicate–treated groups had dust-containing
macrophages scattered throughout the alveolar regions of thelung at the end of the exposure period. Occasional fibers wereseen in animals with exposure to the Calcium Silicate 3. The frequency of dust-containing macrophages declined at the end of
the dust exposure. Fewer dust-containing cells were in animals
exposed to samples C than A or B. The number of animals withinterstitial fibrosis for samples A, B, C, and controls were three,five, five, and five, respectively. In all cases, the alveolar septa
were thickened with abnormal deposits of reticulin and in old
animals with collagen. Although most cells were relatively flatin some areas, some cells were cuboidal and had the appearanceof adenomatosis. Peribronchiolar fibrotic areas were close to therespiratory bronchioles and small granulomatous nodules withmacrophages and fibroblasts were seen in rats exposed to sample
A. Mediastinal lymph nodes from all treated animals showed no
particulate material at the end of exposure. Small primary neoplastic lesions were found in two animals exposed to sample B.
One lesion was described as a small squamous cell carcinoma
and the other as an adenoma. No pathological changes were observed in all other organs. All examined blood parameters were
within normal ranges for both animals studied before and after
exposure (Bolton et al. 1986).
KaolinKaolin was used as a negative control in a previous inhalation
study. The protocol and results are cited under Attapulgite in thissection (Wagner, Griffiths, and Munday 1987).
Zeolite (Synthetic Zeolite A)
A group of 15 male and 15 female Wistar rats were exposed to 20 mg/m3 of Synthetic Zeolite A for 5 h/day, threetimes a week for 22 months. The Zeolite was characterized by(Na12 (Al)2 )(SiO2 )12 ·27H2 O and consisted of particles ranging
from 0.5 to 10 µm. Thirty untreated males were the control
group. Histopathological examinations of the trachea and thelung were completed. Moderate to extensive respiratory disease
was seen in treated and control groups. No neoplasms were observed in any group (Gloxhuber et al. 1983).
In another study by Gloxhuber et al. (1983), a chronic inhalation study of Zeolite A batch F 325 dust was conducted.
Groups of 15 male and 15 female hamsters and 15 male and
15 female rats were exposed for 5-h periods three times a week
for 12 months for hamsters and 22 months for rats. Control animals were exposed to untreated air. The trachea and lungs ofthe animals were examined microscopically. Microscopic examination was limited to the trachea and lungs of 10 treatedhamsters and 8 controls and to 10 treated rats and 5 controls
due to deaths caused by a specific infection. Both species had
moderate signs of respiratory disease in the treated and controls.
In Zeolite-exposed hamsters, macrophages with accumulationsof foreign material were found, mainly in alveoli. No other lesions of inflammation or connective tissue reactions were seen.
Rat lungs had grey-white deposits in macrophages of the alveoli and the peribronchiolar lymph nodes near the hilus. IsolatedDistributed for Comment Only -- Do Not Cite or Quote
SILICATES

clay deposits were found in the mediastinal lymph nodes but noreactions were seen about the deposits.
Zeolite (Synthetic Nonfibrous Zeolite)
Groups of 20 male and 20 female Fischer 344 rats were exposed in inhalation chambers to a mean respirable dust concentration of 0 or 10 mg/m3 of a Synthetic Nonfibrous Zeolite.
Exposures were for 7 h/day, five days/week for 12 months. All
animals were observed for their life span. Three males and threefemales per group were killed at 3, 6, 12, and 24 months after exposure. Erionite and UICC crocidolite were used as positive controls. The mean survival time for animals exposed to
the Zeolite was 797 days, 504 days for animals exposed to erionite, 718 days for animals exposed to UICC crocidolite, and738 days for untreated animals. One pleural mesothelioma andone pulmonary adenocarcinoma were seen in Zeolite-exposed
rats. No neoplasms were found in controls; 27 mesotheliomas
were found in erionite-treated rats and 1 squamous-cell carcinoma of the lungs was found in UICC crocidolite-treated rats
(Wagner et al. 1985).
Dermal Irritation
Hectorite
A primary irritation study patterned after the Draize method
was conducted using six white rabbits. Either a 0.5-ml or a 0.5-g
sample of Hectorite was applied to two sites, one on abradedskin, and the other on intact skin of the backs of the rabbits. The
test sites were occluded for 24 h. At the end of the 24 h, thebinders were removed and the sites were gently wiped clean.
One-half hour later, the sites were examined and scored for erythema and edema. The sites were examined again at 72 h. The
average score was 0.0 and the test subject was nonirritating to
the skin of rabbits (FDRL Inc. 1980a).
Magnesium Aluminum Silicate
VEEGUM (2 g) was applied daily to the external ears offour rabbits for 10 days. These applications were made to bothabraded and intact skin. The abraded skin healed completely
within 4 to 6 days after application. No gross effects were noted
in any of the animals. No tissue was taken for microscopic examination (Munch 1944).
VEEGUM was applied to the closely clipped intact andabraded abdominal skin of two groups of four rabbits each. A
nonabsorbent paper binder was place onto the treated area. The
dose was 3.4 g/kg of body weight. After 24 h, the binder was removed and any residual test material was removed by washing.
Dermal irritation was recorded at 24 h and once daily after application for 7 days. All the animals were killed and necropsy was
performed. No deaths and no systemic toxicity occurred frompercutaneous absorption. The acute dermal LD50 was >3.5 g/kg
of body weight. Dermal irritation generally consisted of moderate erythema and slight edema. The edema completely subsided
within an additional 24 h, and erythema completely subsided in85

all animals between days 2 and 4. No major necropsy findings
were reported (Hazelton Laboratories, Inc. 1968).
Eight male white rabbits were used in a primary skin irritation
test with a solution of 4% MAS; 0.3 ml of the test substance wasapplied to the intact and abraded skin of the backs of four rabbits.
The test substance was applied under occlusive patches for 24 h.
The plaster was removed 24 h after application and the skinreactions were evaluated at 24 and 72 h. The primary irritationindex was 0.1, suggesting that Magnesium Aluminum Silicate
is a weak primary skin irritant (CTFA 1970a).
Three male guinea pigs were used in a cumulative skin irritation test with a solution of 4% MAS (in deionized water). The
test substance (0.05) was applied to the flank of the animals once
daily for 3 consecutive days. Skin reactions were evaluated at
24 h after each application. The cumulative irritation index was
0.0 and MAS had no cumulative skin irritation under the test
conditions (CTFA 1970a).
Sodium Magnesium Silicate
CTFA (1970b) reported a study in which eight male, whiterabbits were used in a primary skin irritation test with a solution
of 4% Sodium Magnesium Silicate (in deionized water). The
test substance (0.3 ml) was applied to the intact and the abradedskin on the backs of four rabbits. The test substance was applied
under occlusive patches for 24 h. The plaster was removed 24 hafter application and the skin reactions were evaluated at 24
and 72 h. The primary irritation index was 0.0, suggesting that
Sodium Magnesium Silicate has no primary skin irritation underthese test conditions.
CTFA (1970b) reported that three male guinea pigs were used
in a cumulative skin irritation test with a solution of 4% Sodium
Magnesium Silicate (in deionized water). The test substance(0.05 ml) was applied the flank of the animals once daily for
3 consecutive days. Skin reactions were evaluated at 24 h after
each application. The cumulative irritation index was 0.0 and
Sodium Magnesium Silicate had no cumulative skin irritation
under the test conditions.
Ocular and Mucosal Irritation
Bentonite
Preparations of Prophypaste, Bentonite, tragacanth, trypsin,and sterile water were injected either intralamellarly or directly
into the anterior chamber of six adult New Zealand rabbits at concentrations ranging from 1 to 5 mg/ml. No significant reactions
were recorded with sterile water, Prophypaste, tragacanth, or
combinations of tragacanth and Bentonite. Bentonite caused severe iritis after injection into the anterior chamber, but no corneal
or retrocorneal reaction was noted grossly or microscopically.
In five of the eyes where Bentonite was injected intralamellarly,
widespread corneal infiltrates and retrocorneal membranes wereobserved within 2 to 5 days. The sixth eye had no reaction, only
0.1 ml of 0.25 mg/ml was injected. Anterior chamber taps ofthe eyes showed viscous mucopurulent material. Microscopic
sections showed pseodoeosinophils, retrocorneal membranes,

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86

COSMETIC INGREDIENT REVIEW

and fibrovascular membranes in the anterior segment. Polarized
light revealed highly birefringent particles were found at the
injections sites, but not in the retrocorneal masses (Austin andDoughman 1980).
Hectorite
A primary eye irritation study using nine New Zealand whiterabbits was carried out according to the Wolcott Procedure. A
0.1-ml liquid or semisolid (100 mg of the solid) sample was instilled into the one eye of each rabbit. Six of the nine animals’eyes were not rinsed and the eyes of three of the animals wererinsed approximately 4 s. All untreated eyes served as controls.
The eyes were then examined with sodium fluorescein and an
ultraviolet lamp at 24, 48, and 72 h and at 7 days. The meanscore at 24 h was 2.0. All subsequent scores were 0.0. The test
sample was considered moderately irritating to rabbit eyes without rinsing and practically nonirritating to the eyes with rinsing
4 s after instillation (FDRL Inc. 1981).
Magnesium Aluminum Silicate
Hazelton Laboratories, Inc. (1968) made a single applicationof 100 mg of VEEGUM or 0.1 ml of a 50% weight/volume to
rabbit eyes. An aqueous suspension was made into the conjunctival sac of the left eye of each of six (undiluted) and three (50%suspension) rabbits. Three eyes (undiluted) were washed for 4 s
after application and the remaining six eyes were not irrigatedbut held closed for 1 s. Control rabbits were not treated. Observations were made at 1, 4, 24, 48, and 72 h and at 4 and 7 days
following application. Irritation was graded according to the
Draize system. On day 7, the eyes were treated with 2% sodium
fluorescein strain to provide evidence of corneal damage. Irritation generally consisted of moderate conjunctival hyperemia
in all eyes and slight iritis in five of the eyes (one in the nonirrigated, undiluted group and two in each of the other groups).
In the nonirrigated eye treated with the dry material, the iritis
persisted until 72 h, whereas it was only present at the 1- and 4-hobservations in the other eyes. The irritation gradually subsided
completely in all within 2 to 4 days. The sodium fluorescein test
was negative for corneal damage.
CTFA (1970a) reported that three male, white rabbits wereused in an eye irritation test using a 4% solution of MAS. The
test substance (0.01 ml) was instilled into the conjunctival sac of
one eye of the animals without irrigation. Acute reactions were
evaluated at 1 and 4 h, and 1, 2, 3, 6, and 7 days after applicationaccording to the Draize scoring system. The average irritation
score at the time of maximum score (1 h) for the cornea, iris,and conjunctivae was 0, 0, and 6.7, respectively. The average
total score was 6.7 suggesting that MAS produced minimal eye
irritation under these test conditions.
Sodium Magnesium Silicate
Three male, white rabbits were used in an eye irritation test
using a 4% solution of Sodium Magnesium Silicate (in deionized water). The test substance, 0.1 ml, was instilled into one

eye of the animals without irrigation. Eye reactions were evaluated at 1 and 4 h, and 1, 2, 3, 6, and 7 days after applicationaccording to the Draize scoring system. The average irritation
score at the time of maximum score (1 h) for the cornea, iris,and conjunctivae was 0, 0, and 6.0, respectively. The average
total score was 6.0, suggesting that Sodium Magnesium Silicate
had minimal eye irritation under these test conditions (CTFA
1970b).
Zeolite (Zeolite A)
In an acute ocular study, rats tolerated a single dose of 10 g ofZeolite A without any adverse reaction (Gloxhuber et al. 1983).
Zirconium Silicate
Gingival tissue was histologically examined in a study conducted by Stookey et al. (1967). Six weanling albino rats were
given an oral prophylaxis using a paste containing 75% Zirconium Silicate and 25% distilled water. The animals were anesthetized and given a routine prophylaxis for 30 s per mandibular
hemijaw. Three of the animals were killed 1 h following treatment. The other three animals were killed 24 h following treatment. Gingival tissue of the buccal surface of the mandibularmolar areas were removed for microscopic examination.
No unusual tissue response was observed in either group. At
1 h, scattered particles of Zirconium Silicate were noted on thesurface of the gingiva. Occasional particles could be identified
in the superficial epithelium. Only an occasional mild local inflammatory response was noted in the subepithelial tissue. It waspresumed to be secondary to the prophylaxis procedure (Stookey
et al. 1967).
REPRODUCTIVE AND DEVELOPMENTAL TOXICITY
Calcium Silicate
FDRL Inc. (1973) conducted a study in which adult, Dutchbelted female rabbits were artificially inseminated and received
oral intubations of Calcium Silicate at doses of 250, 500, 750,
1000, 1250, 1500, and 1600 mg/kg on days 6 through 18 after
insemination. On day 29, cesarean section was performed andthe numbers of corpora lutea, implantation sites, resorption sites,
and live and dead fetuses were recorded. Body weights of live
pups were recorded. The urogenital tracts of the animals were
examined in detail. All fetuses underwent detailed gross examination. Calcium Silicate administered at 1600 mg/kg to pregnant
rabbits for 13 consecutive days had no clear discernible effecton nidation or on maternal or fetal survival. Skeletal or soft tissue abnormalities did not differ from the number occurring incontrol groups.
KaolinGroups of 12 Sprague-Dawley female rats were fed three diets: control diet, 20% Kaolin diet, or iron-supplemented 20%
Kaolin diet. The diets were fed for 37 to 86 days, 69 to 85 days,
and 96 to 117 days prior to fertilization. These same diets were
fed for the duration of the gestation period. The animals fed

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SILICATES

the 20% Kaolin diet had significant reductions in hemoglobin, hematocrit, and RBC numbers, indicating maternal anemia. Significant reduction in the birth weight of the pups wasobserved. Animals fed the iron-supplemented diet maintained
their hematocrit, hemoglobin, and RBC levels (Patterson andStaszak 1977).
Magnesium Aluminum Silicate
According to Sakai and Moriguchi (1975), “MAS has neither
teratogenic nor had adverse effects on the mouse fetus.” MAS
was administered at doses of 600, 3000, and 6000 mg/kg/day
orally to pregnant mice (ICR-JCL) for 6 days on the 7th to12th day of gestation. No significant differences between MASadministered and control groups were observed in body weight
gain, gross lesions, implantations, resorbed or dead fetuses, or
growth inhibition of live fetuses. Incidences of skeletal anomalies were significantly greater in MAS-exposed fetuses, but none
resulted in skeletal malformation. Development, external differentiation, body weight gain, and behavior were normal in alloffspring.
Zeolite (Type A)
Type A Zeolite containing 15.8% sodium 19.0% silicon, and20.1% aluminum was tested for its teratogenic potential by
Nolen and Dickerman (1983). Sprague-Dawley rats and New
Zealand rabbits were utilized under the standard FDA Segment II
protocol. Zeolite A in distilled water was given to rats by gavage
at concentrations of 74 or 1600 mg/kg of body weight on days 6
to 15. Rabbits were given doses of 74, 345, and 1600 mg/kg of
Zeolite A by oral gavage on days 6 to 18. Vehicle controls were
included but no details were provided. Type A Zeolite produced
no adverse effects on the dam, embryo, or fetus in either the rats
or rabbits at any dose.
Zeolite (Clinoptilolite)
Pond and Yen (1983a) investigated whether Clinoptilolite
offers protection against the toxic effect of long-term cadmium
ingestion by examining the effects of long-term ingestion of
Clinoptilolite on reproduction and on the postnatal developmentof the progeny. Four groups of female Sprague-Dawley rats were
fed the following diets: control; control and Clinoptilolite; control plus cadmium; and control plus cadmium and Clinoptilolite.
At 13 weeks, male rats were placed with the females for mating.
The female reproductive performance was unaffected by any ofthe various diets. The supplemental level of Clinoptilolite resulted in reduced body weight during gestation; body weight atparturition and postpartum was similar for rats of all diet groups.
GENOTOXICITY
Attapulgite
DNA damage caused by Attapulgite was evaluated throughthe measurement of unscheduled DNA synthesis (UDS) in a87

study conducted by Denizeau et al. (1985b). Hepatocytes takenfrom male Sprague-Dawley rats were prepared according to thecollagenase perfusion technique. Attapulgite fibers were added
at concentrations of 1 and 10 µg/ml to the primary cultures
2 h after the cells were seeded. 2-Acetylaminofluorene (AAF),
a known UDS-inducing agent of rat hepatocytes, was added
to the cultures at 0.05 and 0.25 µg/ml for each concentrationof Attapulgite. Therefore, Attapulgite was used alone in thisUDS assay system or in combination with AAF. The cultures
were incubated for 20 h. Labeled thymidine was added to final
concentration of 4 µCi/ml. The amount of thymidine in the DNA
was evaluated by liquid-scintillation counting. Cytotoxicity was
also measured in this study by measuring LDH activity using aspectrophotometer.
A significant increase in [3 H]-thymidine incorporation took
place with the addition of AAF (0.05 and 0.25 µg/ml). However,at both Attapulgite concentrations, no significant increase in
DNA-specific activity was observed. No alteration occurred in
the UDS (induced by AAF) by secondary agents when both thefibers and AAF were applied. No statistically significant fiber
effect of AAF-fiber interaction was recorded. Extracellular LDH
activity was observed after 20-h incubations of Attapulgite at 1
and 10 µg/ml applied to the cells. No significant differenceswere found between the LDH activity in the treated samples
versus the controls (Denizeau et al. 1985b).
Beck and Bignon (1985) tested Attapulgite and UICC
chrysotile asbestos B for UDS in primary hepatocyte cultures.
Attapulgite fibers (96%) averaged 0.8 µm in length. Cells werealso exposed to AAF alone and mixed with fibers. Within 20 h,both types of fibers were found in various cell structures, i.e.,
plasma membrane invaginations, cytoplasmic vacuoles, andphagolysosome-like components. Chrysotile B and Attapulgite
did not induce a significant UDS response or modulate the response to AAF.
The UDS and cellular growth was studied utilizing rat pleural
mesothelial cells (RPMCs) in a study conducted by Renier et al.
(1989). RPMCs were cultured to confluence on glass coverslips
in multiwell plates. Concentrations 2, 4, and 10 µg/cm2 of Attapulgite and [3 H]-thymidine were added to cultures for 20 h.
UDS was not modified at concentrations of 2 and 4 µg/cm2 ofAttapulgite. However, in one experiment, 10 µg/cm2 produced
a significant increase in UDS. Cellular growth was measured
by counting in situ with an inverted phase-contrast microscope
after 24 h of treatment of 1, 2, 4, and 10 µg/cm2 of Attapulgite.
Results were similar to that of the UDS. Attapulgite was considered noncytotoxic at concentrations of 1, 2, and 4 µg/cm2 .
However, at 10 µg/cm2 , cell growth was inhibited. No specificdetails were given.
Adachi et al. (1992) studied the effect of asbestos fibers on
DNA by measuring the yield of 8-hydroxy-20 -deoxyguanosine(8-OH-dGuo). 8-OH-dGuo is an OH adduct at the 8-positionof a guanine base thought to induce an AT-to-GC transversion in DNA which may lead to a point mutation. For comparison purposes, Attapulgite was also studied. Results forDistributed for Comment Only -- Do Not Cite or Quote

88

COSMETIC INGREDIENT REVIEW

Attapulgite were not different from controls (Adachi et al.
1992).
Calcium Silicate
Litton Bionetics, Inc. (1974) conducted a study in which FDA
compound 71-41, hydrated Calcium Silicate, was suspended
in 0.85% saline at concentrations of 1000, 500, 200, 100, and10 µg/ml and applied to WI-38 cells in a logarithmic phase of
growth. The cells were observed for cytopathic effects (CPEs)
and the presence of mitosis at 24 and 48 h. Inhibition of mitosis
was observed at all concentrations except 100 and 10 µg/ml. A
closer range of concentrations, 200, 150, 100, 75, and 50 µg/ml,
were employed and tested for the same findings. Mitosis was
stopped only in the cells dosed at 200 µg/ml.
FDA compound 71-41, hydrated Calcium Silicate, was also
tested for mutagenic properties in a host-mediated assay using
the microorganisms Salmonella TA-1530 and G-46 and Saccharomyces D3. These experiments were carried out in mice orally
administered (acute and subacute) 15, 150, and 1500 mg/kg of
Calcium Silicate. No increased mutation frequencies were seenin Salmonella TA-1530 or G-46. Saccharomyces D3 had no significant increase in recombinant activity. In fact, a reduction inrecombinant activity was produced by the compound. In a second host-mediated assay, Calcium Silicate was administered at5000 mg/kg to mice against Salmonella TA-1530 and G46 andSaccharomyces D3. All tests were negative.
Cytogenetic studies in vivo examined bone marrow cells arrested in C-metaphase from rats exposed to FDA compound71-41, Calcium Silicate. Rats were administered 15, 150, and1500 mg/kg doses. The positive-control was triethylene
melamine (TEM) and the negative-control was saline. The chromosomal abnormalities observed in the positive-control animals
were significantly greater than those of either the negative control or the compound. The maximum effect of the positive control was observed at 48 h after administration. Calcium Silicate
produced breaks in the range of 1% to 3% in all three acutedosage levels. However, these were not significantly higher than
the negative controls. The subacute dose of 150 mg/kg produced
breaks at 3%. The negative-control breaks were consistent withthose of other experiments.
These same cytogenetic tests were observed in vitro. Cells(not specified) were observed in anaphase for chromosomal
aberrations such as bridges, psuedochiasmata, multipolar cells,
acentric fragments, etc. Doses of Calcium Silicate were as follows: 1.0, 10.0, and 100.0 µg/ml. Controls, both positive andnegative, were the same as reported above. The positive control produced significantly greater percentages of chromosomal
aberrations than the negative control or test compound. There
were no aberrations observed due to Calcium Silicate.
In a third cytogenetic test, Calcium Silicate was administered
to male rats in one dose and in five doses of 5000 mg/kg. A
positive-control, TEM, and a negative-control, saline, were also
tested. Metaphase spreads were prepared from the bone marrowcells of these animals and scored for chromosomal aberrations.

Neither the variety nor the number of the aberrations differedsignificantly from the negative controls. Calcium Silicate was
nonmutagenic.
Dominant lethal assays were carried out in male rats administered FDA compound 71-41, hydrated Calcium Silicate, atdoses of 15, 150, and 1500 mg/kg, both as one dose and as fivedoses. Also tested were the negative saline control and a positive
TEM control. This assay measures the amount and type of fetal
wastage that may occur following administration of a potential
mutagen. Each treated male rat was mated with two virgin female rats each week for eight (acute) or seven (subacute) doses.
Two weeks after mating, the female rats were sacrificed andthe fertility index, preimplantation loss, and lethal effects were
determined and compared with the same parameters calculated
from the negative and positive controls. No significant findings
were observed in the fertility index or preimplantation loss. The
test compound was also administered at a dose of 5000 mg/kg.
The protocol was the same as listed above. All parameter values did not differ significantly from that of the negative control.
Comparing the data of both experiments indicates that hydrated
Calcium Silicate does not induce dominant lethal mutations(Litton Bionetics, Inc., 1974).
Hectorite
Hectorite suspended in dimethylsulfoxide (DMSO) at concentrations of 10 to 3000 µg/plate was subjected to spot test using five mutant strains of Salmonella typhimurium LT2, hisTA98,
hisTA100, hisTA1535, hisTA1537, and hisTA1538, with andwithout metabolic activation. Positive controls were carried out
utilizing Aroclor 1254. Hectorite was nonmutagenic in all fivetest strains (Inveresk Research International 1995).
Magnesium Aluminum Silicate
MAS was subjected to spot test using five mutant strainsof S. typhimurium LT2, hisTA98, hisTA100, hisTA1535,
hisTA1537, and hisTA1538. Positive and negative controls werecarried out utilizing S9 mitochondrial preparations from the livers of Sprague-Dawley rats and 2-aminoanthracene. MAS was
found to be nonmutagenic in all five test strains (Blevins andTaylor 1982).
ZeoliteDurnev et al. (1993) tested the clastogenic potential of Zeolite particles <10 µm in length in peripheral human blood
lymphocytes. Chrysotile fibers were used as a positive control.
Both fibers produced statistically significant increases in the percentage of aberrant metaphases, mostly from chromatid breaks.
Superoxide dismutase (50 µg/ml) protected against the induction of aberrant metaphases by chrysotile asbestos, but not by
Zeolite. However, catalase (20 µg/ml) protected against induction of aberrant metaphases by Zeolite, but not by chrysotile
asbestos.
Chromosomal aberrations in cells of C57BL/6 mice were also
investigated. The cells were collected by peritoneal lavage andDistributed for Comment Only -- Do Not Cite or Quote
SILICATES

from the bone marrow of mice and were sampled at 1, 2, 7, and28 days after the intraperitoneal injection of 100 µg/mouse natural Zeolite particles. Chrysotile asbestos was used as a positive
control. The lavage sample contained 20% lymphocytes, 20% to
30% macrophages, and 50% to 60% PMN leukocytes. The injection of the Zeolite induced a statistically significant increase inaberrant metaphases after 7 and 28 days in the peritoneal lavage
cells. Chrysotile induced the aberrant metaphases at all times inboth the peritoneal lavage and bone marrow cells (Durnev et al.
1993).
Valatina, Pylev, and Lemjasev (1994), tested the clastogenic
effect on bone marrow cells of five dust samples from Zeolite
tuffs. Presterilized dusts were administered intraperitoneally to
BALB/C mice. The known clastogen mitomycin C was used asa positive control and 0.5 ml of saline as a negative control. The
animals were killed 24 h after administration and mice bonemarrow samples were taken. Polychromatophilic erythrocytes(PCEs), which contain micronuclei that are formed during mitosis on acentric fragments of the chromosomes as a result of
clastogenic actions, were counted. Many of the dust samples
were as potent a clastogenic agent as mitomycin C. A summaryof the results is listed in Table 21.

CARCINOGENICITYThe IARC (1997) has placed Attapulgite fibers >5 µm inGroup 2B, possibly carcinogenic to humans. Fibers <5 µm
cannot be classified as to their carcinogenicity to humans andwere classified in group 3. The Utrecht University’s Institute for
Earth Sciences and Vening Meinesz Institute for Geodynamic
Research (Englehard 1998) analyzed Engelhard’s Attapulgite
clay by transmission electron microscopy to determine the fiber
length. The transmission electron microscopic analytical results
was <5 µm.
TABLE 21Micronuclei induced by Zeolite tuffs (Valatina, Pylev, andLemjasev 1994)
Administeredsubstance
Dust 1Dust 2
Dust 3
Dust 4
Dust 5
Mitomycin C
Saline control

Dose(mg/g)

Amount of PCEs withmicronuclei (per 1000 PCEs)

2.0
0.8
1.4
2.1
3.15
1.26
2.15
.86
3.25
1.3
0.16 mg/kg
0.5 ml8.33 ± 0.5
5.83 ± 0.5
2.83 ± 0.3
3.83 ± 0.6
0.5 ± 0.8
3.8 ± 0.5
6.7 ± 0.5
5.2 ± 0.5
4.83 ± 03.66 ± 0.5
7.70 ± 0.3
2.70 ± 0.03

89

Clinoptilolite, Phillipsite, Mordenite, Nonfibrous JapaneseZeolite, and synthetic Zeolites cannot be evaluated as to theircarcinogenicity to humans (group 3) according to the IARC
(1997).
Table 22 is a summary of carcinogenicity data, which weredetailed earlier in the section Animal Toxicology.
CLINICAL ASSESSMENT OF SAFETY
Dermal Irritation
Magnesium Aluminum Silicate
Applications of 2 g of VEEGUM were made to the skin of
two human subjects in an 1-inch area daily for 1 week. No effects
were noted and no other details were given (Munch 1944).
Inhalation
Aluminum Silicate
Musk et al. (1980) surveyed 17 workers exposed to the Aluminum Silicate dust, alunite. Respiratory questionnaires and occupational history, pulmonary function testing, and posterioanterior chest radiographs were obtained. The alunite chemical
analysis was that 48.5% of it was Al2 O3 and 35.0% was SiO2 .
The average age of the subjects was 29.1 years. The mean transfer factor for carbon monoxide (TL ) predicted for the wholegroup was 85.8% and the mean ratio of TL to effective alveolar
volume (V A ) was 83.8%. The actual group TL and TL /V A wasless than predicted. Overall, the group had comparable predictedlevels of forced expiratory volume (FEV) in 1 second, vital capacity (VC), and total lung capacity (TLC). Two subjects had
small irregular opacities on chest films. Neither of these subjects
had previous exposure.
Attapulgite
Churg (1983) surveyed the total pulmonary nonasbestos mineral content in 20 patients who had no occupational dust exposure. The lungs were autopsied and 3- to 5-g pieces were dissolved in bleach and the treated sediment was transferred to aelectron microscope grid. Mineral fibers were identified using
electron diffraction and energy dispersive x-ray spectroscopy.
No correlations were between numbers or types of fibers andage, sex, or smoking. Attapulgite was identified in 12/20 patientsand approximately 8400/106000 fibers (7.9%) were Attapulgite.
Further mineralogical analysis revealed 100% of the Attapulgite
fibers were 1 to 4.9 µm in length.
KaolinChurg (1983) surveyed the total pulmonary nonasbestos mineral content in 20 patients who had no occupational dust exposure. The lungs were autopsied and 3- to 5-g pieces were dissolved in bleach and the treated sediment was transferred to anelectron microscope grid. Mineral fibers were identified using
electron diffraction and energy dispersive x-ray spectroscopy.
No correlations were between numbers or types of fibers andDistributed for Comment Only -- Do Not Cite or Quote

90

COSMETIC INGREDIENT REVIEWTABLE 22
Summary of carcinogenicity data
ProcedureSingle intrapleural injections offour samples into rats (lived life span)Single intraperitoneal injections into
rats (lived life span)
Chronic inhalation exposure for 1 year
in rats

Single intraperitoneal injections into rats
Single direct pleural application toleft pleural surface of rats
(killed 2 years later)
Single intrapleural injections into rats
(lived life span)Single intraperitoneal injections into
rats (lived life span)Single intrapleural injections into rats
(lived life span)Single intrapleural injections into rats
(lived life span)
3 samples were injected one time eachweek for 9 weeks into rats (surviving
animals were killed at 2.5 years)
Single intraperitoneal injections wereadministered for 3 weeks in rats
(killed at 2.5 years)
Inhalation chamber exposure to rats for
6 h/day for 5 day/week (killed at 3, 6,
and 12 months)

Oral administration for 104 weeks
in rats
Single intratracheal instillations into rats
(killed at end of study)
Single intraperitoneally injections intomice (10 month study)
Single intraperitoneal injection into
mice

Dose/concentration

ResultReference

Aluminum Silicate
20 mg (0–40 µm)
3 malignant mesotheliomas(1 pleural and 2 peritoneal)
Calcium Silicate
25 mg
Little dust or dust-related fibrosis
was visible; no mesotheliomas
Interstitial fibrosis,
10 mg/m3
1 small squamous cell
carcinoma, 1 adenoma inlungs
Attapulgite
25 mg
Tumor incidence rate was 67%
40 mg

17/615 of treated rats developed
pleural sarcomas

20 mg/ml of 0.9% NaCl
(0.77 µm)
No concentrations given(fiber lengths ranged
from 0 to 25 µm)
20 mg (0.77 µm)

No mesothelial neoplasms ineither control or treated rats
46 mesotheliomas

0.5, 2, 4, 8, 16, or 32 mg(<1 µm)60 mg (0.04 to 0.8 µm)

Pigott and Ishmael
1992
Bolton et al. 1986
Bolton et al. 1986

Pott, Huth, andFriedrichs 1974
Stanton et al. 1981

Jaurand et al. 1987
Wagner, Griffiths,
and Munday 1987

No mesotheliomas

Renier et al. 1989

2/140 had mesotheliomas

Coffin, Cook, andCreason 1992
Pott et al. 1987

Noncarcinogenic results for all
three samples

2, 4, and 4 mg (1.3 and0.07 µm)

40% of 30 rats had neoplasms

Pott et al. 1987

10 mg/m3

2 mesotheliomas, 2 peritoneal
mesotheliomas, 1 malignant
alveolar neoplasm, 2 benign
alveolar neoplasms, 11
bronchoalveolar hyperplasias

Wagner, Griffiths,
and Munday 1987

No incidence of neoplasticchangesNo significant increase in theincidence of any specificneoplasm
No neoplastic changes wereobserved
Mild peritoneal fibrosis but noneoplasms

Gloxhuber et al.
1983
Tatrai and Ungv’ary
1983

Zeolite1, 10, 100, or 1000 mg/kg
30 and 60 mg (< 5 µm)
10 or 30 mg (< 5 µm)
10 mg (<3 µm)

Suzuki 1982
Suzuki andKohyama 1984
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91

SILICATESTABLE 22
Summary of carcinogenicity data (Continued)
ProcedureSingle intraperitoneal injections
into mice (7–23-month exposure)
Single intrapleural injection into
rats (chronic study)
Single intraperitoneal injections
into rats (141 weeks)Single intrapleural injections in rats

Dose/concentration

ResultReference

10 mg (2.24 µm)

No mesotheliomas observed

Suzuki and Kohyama 1984

20 mg

1 pleural and 1 peritoneal
mesothelioma
1 peritoneal mesothelioma

Wagner et al. 1985

25 mg
25 µm

Single subcutaneous injections

25 µm

3 intrapleural injections were given
in monthly increments to rats
3 intrapleural injections were given
in monthly increments to rats
Inhalation exposure to rats for 7
h/day, 5 days/week for 1 year
(lived life span)

20 mg (3 to 500 µm)
20 mg (5 to 100 µm)
10 mg/m3

age, sex, or smoking. Kaolin was identified in 12/20 patients andapproximately 3500/106000 (3.3%) fibers were Kaolin. Further
mineralogical analysis revealed 94% of the Kaolin fibers were
1 to 4.9 µm in length.
Morgan et al. (1988) surveyed and studied the prevalenceof ventilatory impairment, chest symptoms, and radiographic
abnormalities in over 2000 Kaolin workers representing over
95% of the current employees in the industry. Of the participants, 19% admitted having a cough. Of those participants witha cough, 17% had an abnormal FEV and 14% had an abnormal
VC. Of those without a cough, 5.5% had an abnormal FEV and
7% had an abnormal VC. Also, 18% of the participants admitted
to chronic sputum production. Of those with sputum production,
16% had abnormal FEV, and 12.5% had abnormal VC. Of those
without the production, 6% had an abnormal FEV, and 7.5% had
an abnormal VC. About 30% of the participants complained ofshortness of breath, 3.1% was classified as severe. Wheezing
was reported by 29% of the subjects. Satisfactory chest films
for 2069 of the subjects were available for examination. Radiographic findings of 90 subjects revealed simple pneumoconiosis.
Of these cases, 3.16% had category 2 pneumoconiosis, 1.0% had
category 5, and 0.25% had category 3. Eighteen subjects (0.89%)
had complicated pneumoconiosis. Of these cases, five had stage
A, eight had stage B, and five had stage C. Of men with eithercase of pneumoconiosis, 51.1% were dry processors, compared
to 6.3% of the men who worked in wet processing. Of the nonsmoking participants (549), 542 and 537 men had a satisfactory
FEV and forced vital capacity (FVC), respectively, in addition toan acceptable chest radiograph. Of these nonsmoking workers,

No difference in tumor incidence
between control and treatedgroupsNo difference in tumor incidence
between control and treatedgroups2 mesotheliomas and 1 bronchial
carcinoma/93 treated animals
Neoplasms were found in 41/101
animals
1 mesothelioma and 1
pulmonary adenocarcinoma

Maltoni and Minardi 1988
Maltoni and Minardi 1988

Maltoni and Minardi 1988

Pyev et al. 1986
Pyev et al. 1986
Wagner et al. 1985

516 were studied for dust exposure and pulmonary function.
Among the nonsmokers with no pneumoconiosis, those persons
working in calcined clay had a greater prevalence of lung function abnormalities. This group had a significant increase in therisk of having an abnormal FEV but tended to have less incidences of pneumoconiosis. In short, ventilatory impairment was
related to the presence of complicated pneumoconiosis, employment in clay calcining, and cigarette smoking. Also work in
dry processing was associated with a greater risk of developing
pneumoconiosis (Morgan et al. 1988).
Waxweiler et al. (1988) evaluated the possible health effects of occupational exposure to Attapulgite. A cohort studyof 2302 men employed for at least 1 month at an Attapulgite
mining and milling facility was followed through 1975. A significant deficit of mortality from nonmalignant respiratory disease (NMRD) was observed based on age, calendar year, andrates was observed. A marked deficit of NMRD was seen regardless of presumed dust exposure level, induction-latency period,or duration of employment. A statistically significant excess ofmortality from lung cancer was observed among whites, but adeficit occurred among nonwhites. Lung-cancer risk in either
race was not altered substantially with presumed dust exposurelevel, induction-latency period, or duration employed, with one
exception—those employed for at least 5 years in high-exposurelevel jobs. An increased mortality was observed for gastric cancer (six observed) and a deficit due to nonmalignant respiratory
disease was observed (nine observed).
The lungs of 62 recently deceased men between the yearsof 1968 to 1981 were taken for an assessment of the severity

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92

COSMETIC INGREDIENT REVIEW

of lung disease (Wagner et al. 1996). Fifty-four of the 62 men
worked with china clay or china stone. All the test subjects were
employed in the mining industry. Test subjects were divided into
groups according to their contact with the minerals: dusty china
clay; wet, nondusty china clay; china stone; other dusty environments. The authors of this publication define china clay as“consisting mainly of the mineral kaolinite and in most othercountries it is referred to as Kaolin.” China stone “consists essentially of a mixture of quartz, feldspars, micas, and amorphoussilicon dioxide.” Chest radiographs were available for 39 of the
62 cases. Sections of lung tissue were examined microscopicallyfor nodular and interstitial fibrosis and an overall grade ranging
from 0 (none) to 3 (severe). Samples from 42 cases were analyzed for mineral content by x-ray diffraction and lung-dustconcentrations.
Radiographic lesions included 13 cases of progressive massive fibrosis and 22 cases of simple pneumoconiosis. Only fourcases had no evidence of any disease. Nodular opacities tended
to reflect a high quartz content, whereas high-Kaolin lung content had interstitial changes and irregular radiological changes.
Mineralological analysis of the 42 cases revealed two separate
groups of mineral composition and one miscellaneous group.
The china clay group was composed of ≥90% Kaolinite in its
samples consisted of 16 cases. The other distinct group, the clay
and stone group, was composed of <90%; Kaolinite and greatercontents of subsidiary components including quartz comprised
16 cases. The other group had a large variation of mineral composition. Lung-dust concentrations were greatest in the china
clay group as shown in Table 23.
The grades of nodular fibrosis ranged in the china clay groupfrom 0 (none) to 2 (moderate—up to 7 nodules/section or nodules of 3 to 6 mm in diameter). In china stone/clay group half,
8 of 16, were grade 3 (severe—more than 7 nodules/section or
6 to 10 mm in diameter). An increasing quartz concentration
appears to be related to nodular fibrosis. Interstitial fibrosis ingroup ranged from 1 (slight—fibrosis located around respiratory
bronchioles, which may extend into alveolar ducts and adjacentalveoli, but with areas remaining free of fibrosis between adjacent respiratory bronchioles) to 3 (severe—widespread diffuse
fibrosis with few recognizable alveoli; honeycomb may or may
not be present). No correlation was found between Kaolinite
concentration and interstitial fibrosis grades; however, the china
TABLE 23
Dust concentrations in lung tissue of deceased men who
worked in the mining industry (Wagner et al. 1996)
Lung dust concentrations (mg/g)
Mineral group

Minimum

Maximum

MedianChina Clay (a)China Stone/Clay (b)Miscellaneous (c)

7.6
4.1
1.6

289.3
44.8
28.7

40.0
15.0
6.5

clay group had little exposure to anything but china clay. The degree of interstitial fibrosis appears to be more related to dust lungconcentrations, although these results failed to reach statisticalsignificance (Wagner et al. 1996).
The ACGIH does not classify Kaolin as a human carcinogenand gives a TLV-TWA of 2 mg/m3 for respirable dust and total
dust (ACGIH 1997).
Zhang, Zhang, and Song (1997) reported the results of environmental monitoring and health surveillance performed on 781
Pyrophyllite miners and Pyrophyllite dust carvers from the yearsof 1954 to 1986. Routine radiographs of the workers lungs werestudied for lesions of pneumoconiosis. The PM workers weredivided into three groups, manual drillers (A), mechanical dry
drillers (B), and mechanical wet drillers (C). The PCM workers
were divided in two groups, carvers in factories (A) and carvers
working at home (B).
PM workers, group B, had a greater incidence (43.5%) of
pneumoconiosis than all other groups. In order to exclude theeffect of the duration of exposure (DE), the DE-adjusted prevalence rate was calculated. The DE-adjusted rates are as follows,
PM groups, 36.6% and PCM groups, 14.4% of pneumoconiosis(Zhang, Zhang, and Song 1997).
Case Reports
Aluminum Silicate
Sherwin (1979) found abnormal numbers of birefringent particles in the lungs of seven patients: five vineyard workers, one
farmer, and one rural resident. A spectrum of early-to-late interstitial inflammation and fibrosis were seen. Nodular granulomas
seen in silicosis were absent. Mineralogical analysis revealed
mostly silicates, i.e., aluminum and potassium silicate.
Musk, Greville, and Tribe (1980) reported a case of a42-year-old woman who had no history of previous exposure to
Aluminum Silicate dust until she started working at an aluniteresidue bagging mill. Chemical analysis of the alunite-residue
showed 48.5% of constituents to be Al2 O3 and 35.0% to be
SiO2 . Eight months after working, she noticed the onset of dry
cough and shortness of breath. Within 3 months these signs
lasted throughout the day. She remained working for 18 months
and after leaving work, the cough completely subsided within
3 months. She also complained of pain and morning stiffness injoints, wrists, elbows, and right knee. Corticosteroid treatment
was started after a lung biopsy. A chest film taken 3 months after the onset of symptoms had lesions of diffuse small irregularopacities throughout both lungs. Subsequently, pulmonary function tests revealed a decrease in transfer factor for carbon monoxide (TL) and effective alveolar volume (TL/VA) and abnormaltranspulmonary pressure–lung volume relationships. Pulmonary
lesions included examination interstitial infiltration with smallround cells, variable fibrosis, and scattered granulomas. Alveoli
were distorted and the granulomas were moderately well formed
with multinucleate giant cells and epithelioid histiocytes. Aftercorticosteroid treatment, no increase in severity of the lung lesions was seen.

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93

SILICATES

Calcium Silicate
A 23-year-old man was involved in the bagging process ofa food additive. The food additive produced a white thin layerof powder that continuously covered the work floor. An antibiotic, carboxymethylcellulose, and Calcium Silicate comprised
the food additive. On the third day of working, the patient experienced an itchy eruption on his face, neck, and forearms.
The rash was erythematopapular with no vesicles. The redness
was not diffuse and patches of erythema and papules were confluent on the neck and forearms. All signs faded the following
morning. The rash occurred again when the patient returned towork. Patch tests were performed using the food additive, an antibiotic, carboxymethylcellulose, and Calcium Silicate. All tests
were negative and there were no clinical signs of irritation at thetest sites. No late reaction was recorded either. A sample of thefood additive was examined under the microscope. Analysis revealed sharp-edged particles corresponding to Calcium Silicate.
It was determined that the Calcium Silicate dust caused an “airborne irritant contact reaction.” The problem was eliminated byincreasing the humidity in the workplace and aspirating the air(Lachapelle 1984).

Bentonite
Phibbs, Sundin, and Mitchell (1971) reported many casestudies involving Bentonite workers. Some milling plants had
dangerous concentrations of silica that ranged from 2 to 10
times the safe maximal concentration according to the U.S.
Bureau of Mines. Silicotuberculosis developed in four patients
studied.
Austin and Doughman (1980) reported a 20-year-old dental
assistant who noted a foreign body in her right eye after usinga drill to polish a patient’s teeth with Prophypaste. Immediately
she noticed decreased vision and photophobia. Several opaquedeposits superficially embedded in her right cornea were removed within 2 h. There was no evidence of corneal perforation
or iritis. A residual superficial corneal infiltrate was noted paracentrally. An anterior uveitis developed and was treated. One
month after the injury, the cornea was edematous with a superficial, peripheral ringlike stromal infiltrate and a deep inferior
stromal infiltrate. A retrocorneal abscess was present. There wasno eyelid edema present. Culture results were negative. Anterior
segment inflammation, progression of the corneal edema, andan enlarged ring abscess in the corneal stroma continued. There
was complete loss of red reflex and iris detail. The diagnosis
was infectious endophthalmitis and anterior chamber and vitreous aspirations were performed. No organisms were seen but
a few PMN leukocytes were present in the aspirations. Theseauthors undertook the toxicity studies in rabbits presented in theocular animal toxicity section under Bentonite. They concluded
that the similarity of the findings in animals after injection of
Bentonite with the findings in this case report suggested that
Bentonite was the responsible agent in the dental assistant’s
symptoms.

Fuller’s Earth
Tonning (1949) reported a man having worked in a Fuller’s
Earth plant as a young man. The length of employment wasestimated at no more than 15 years. He was diagnosed withterminal aspiration pneumonia, pneumoconiosis due to Fuller’s
Earth exposure, bilateral emphysema, and fibrous pleural adhesions. Lesions differed from typical silicotic lesions of the lungs;
no formations of the whorled, acellular collagen typical of silicotic nodules were observed. Isolated cavities in the apices werefilled with black sludge and surrounded by vascular and cellular collagen. The dust in the lymph nodes had only stimulated
the formation of reticulin fibers. No subpleural nodules were
present. At mineralogical analysis, the Fuller’s Earth deposits
were constituted mainly of Montmorillonite (85.2% to 90%).
Sakula (1961) reported two cases of pneumoconiosis due toFuller’s Earth (Table 24). Mineralogical analysis of the Fuller’s
Earth established Montmorillonite as the major component.
KaolinLynch, Harrison, and Nagelschmidt (1954) investigated twocase studies of men who worked in a Kaolin-processing plant
for many years. The lungs of the two persons and chest x-ray
films were evaluated. The first case was a 36-year-old man who
worked on the plant for 17 years. Chest films were taken at theend of his career and detected lesions of extensive confluent
consolidation and nodule formation of advanced pneumoconiosis with infection. Autopsy and microscopic findings included
alveolar spaces uniformly expanded, three areas of whorled fibrous tissue, scattered areas of cystic spaces, hilar nodes heavily pigmented, deposits of brownish black particulate matter,a large vessel with recent thrombus, hemorrhage, and necrosis, marked fibrous thickening of the pleura, and dense fibrousscarring of the lymph nodes. The final diagnosis was pneumoconiosis (kaolinosis) with pulmonary thrombosis and infarctionof the lungs. The second case study was a 35-year-old man
who worked in a Kaolin-processing plant for 21 years. Within
his last 3 years, he had dyspnea and a slight cough with small
TABLE 24
Pneumoconiosis cases reportedly linked to exposure
to Fuller’s Earth (Sakula 1961)
Patient

Symptoms

Male who worked
in a Fuller’s Earthprocessing plantfor 42 years

Fine to medium miliary mottlingof both lungs; sputum
examinations were negativefor M. tuberculosis; slowly
deteriorating pulmonary
function; recurrent bronchitis
Chronic cough and sputum; finemiliary mottling throughout
both lungs; increasing
dyspnea

Male who worked for
28 years in milling

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94

COSMETIC INGREDIENT REVIEWTABLE 25
Pneumoconiosis cases reportedly linked to exposure to Kaolin (Hale et al. 1956)
Patient

Symptoms

Diagnosis

44-year-old man; worked in a Kaolin millfor 28-years

Cough with thick white sputum; easily dysponeic on slight
exertion; well-marked nodulation of silicotic type withcoalesence of the nodules in several areas and emphysema
Several years of a productive cough; emphysema;massive fibrosis on both sides; no evidence of neoplasm
Diffuse nodular mottling with considerable attenuationof the bronchovascular markings
Fine miliary mottling in both lungs; well-marked calcification
at the left hilum
Small discrete nodular mottling with an increase in the rootshadows and the lung markings
Cough and shortness of breath; emphysema; definite nodular
mottling

Pneumoconiosis

67-year-old man; worked in china clay
bagging for nearly his entire life
44-year-old man; worked in china clay
bagging for nearly his entire life
39-year-old man; worked 14 years
with clay
73-year-old man; worked 12 years
in open limestone quarries
64-year-old man; 43 years loading
china clay

amounts of dark colored sputum. The sputum was negative forbacteria. Chest films revealed advanced pneumoconiosis with infection, confluent consolidation, nodular infiltration, cavitation,and emphysema. Autopsy and microscopic findings included
nodules in the right and middle lobes, pleural spaces were thickened and shaggy, large bulbous emphysematous blebs, a pulmonary artery with organizing thrombus, heavily pigmented hilar lymph nodes, whorled fibrous collagenous tissue, and spaces
and walls with macrophages. The final diagnosis was pneumoconiosis (kaolinosis).
Hale et al. (1956) reported six cases of pneumoconiosis due
to Kaolin. These are given in Table 25 and not further discussed
here.
Butz (1970) reported that a 47-year-old man who was achronic intravenous drug user died from tetanus. The man had
been injecting paregoric, a camphorated opium tincture containing 35 to 46 mg of morphine per 100 ml. Paregoric can be foundin proprietary preparations that do not require prescriptions; intravenous drug users often attempt to separate the paregoric fromthe Kaolin. Often the injection of Kaolin, either through shunts
in the lung of an intravenous drug user with obliterative pulmonary arteritis and angiomatoid formations or by extrusionfrom the arterial lumen and transfer to the pulmonary veins, allows the Kaolin crystals to go into the peripheral circulation.
In this patient, numerous skin abcesses were noted on the neck,shoulders, upper extremities, chest, thighs, and lower extremities. In skin sections, the lesions were multiple foreign body
granulomata and large birefringent crystals. Adhesions over thepleural surface of the lungs were also noticed. At microscopic
examination the lungs had foreign body granulomata within thepulmonary arterioles. Extensive pulmonary edema and massesof pigmented histiocytes filled the alveolar spaces. Extensive
periportal fibrosis was seen in the liver. The central nervous system lesions were extremely fine, double refractile particles innerve bundles entering the anterior roots in the central region.

Pneumoconiosis
Pneumoconiosis
Pneumoconiosis
Pneumoconiosis
Pneumoconiosis

Herman, Olscamp, and Weisbord (1982), reported a patientwith multiple pulmonary Kaolin granulomas. The man had a history of bilateral recurrent pneumothorax. Both pleural spaces
were destroyed with a suspension of liquid Kaolin. Recurrent
right-sided pneumothorax devolved and reobliteration was again
performed. In a follow-up chest radiograph, multiple welldefined peripheral nodules were in both lungs and pathological analysis revealed a bland acellular material surrounded bychronic inflammatory cells. By light microscopy, the particles
were consistent with Kaolin. It was presumed that Kaolin
entered the lungs through pleuroalveolar or pleurobronchial
openings.
Lapenas and Gale (1983) reported that a 35-year-old man who
worked at a Kaolin-processing plant for 17 years complained ofchest pain and was hospitalized. For the previous 2 years before admittance, the man had packaged dried, processed Kaolin.
Chest films revealed diffuse reticulonodular pulmonary infiltrates and a well-defined, noncalcified mass in the upper rightlobe. A thoracotomy was performed and an 8 × 12 × 10-cm
conglomerate pneumoconiotic lesion containing large amountsof Kaolin was found. X-ray diffraction material from the lesion
had peaks corresponding to Kaolinite. The presence of silica
was not confirmed by x-ray diffraction.
Lapenas et al. (1984) obtained pulmonary tissue from five
Kaolin workers with advanced pneumoconiosis. Chest radiographs detected small irregular shadows and large opacities typical of Kaolin pneumoconiosis. At autopsy, firm, grey-brown
nodules and masses were in the parenchyma and in the hilar
lymph nodes. Microscopic lesions were extensive pulmonary
Kaolinite deposition associated with the formation of peribronchiolar nodules. The nodules were comprised of Kaolinite aggregates transversed by bands of fibrous tissue rather than dense
whorled collagen. Kaolin was detected in the lungs. Silica was
not detected by either analytical scanning electron microscopy
or x-ray diffractometry.

Distributed for Comment Only -- Do Not Cite or Quote
SILICATES

Levin et al. (1996) investigated the death of a 62-year-old
man who worked in a cotton textile mill for 43 years. The patient complained of progressive dyspnea and a productive cough.
After being admitted to the hospital, a bronchoscopy was performed and no endobronchial lesions were found. A lung biopsy
had lesions of severe interstitial fibrosis with bronchioalveolar
structures extensively involved in the fibrotic process. Pathological alterations such as bronchiolectasis, interstitial fibrosis withthickening of alveolar septa, mobilization of macrophages, andmultinucleated giant cells were identified. Neither ferruginous
bodies nor pleural hyaline plaque was identified. Kaolin particles
were present with a mean size of 0.88 µm. Chrysotile asbestos
was also detected, but the majority of particles were Kaolin.
The man died as a consequence of respiratory failure despite anaggressive therapy of antibiotics and tuberculosis therapy.
Magnesium Trisilicate
Lee et al. (1993) reported a case of a 30-year-old female witha long-term history of ingesting trisilicate-containing antacids.
The patient had repeated attacks of renal colic but the presenceof calculi could not be determined by intravenous pyelography
nor ureteroscopy. X-ray diffraction did detect a silicate stone.
The patient stopped taking trisilicate containing products. The
frequency of stone passage decreased and the renal colic wasrelieved.
Montmorillonite
A 73-year-old Montmorillonite worker developed signs ofpneumoconiosis. A chest radiograph was taken 2 years before
his death and a bilateral fine reticulonodular shadowing wasobserved. The man died of acute gastrointestinal hemorrhage
from a benign gastric ulcer. A few weeks before his death another chest radiograph indicated a slight increase in the reticulonodular opacities and a mass at the left hilum and apex.
At autopsy, numerous soft stellate grey-black dust lesions 4 to
5 mm in diameter that occupied most of the lungs were found.
No lesions of progressive massive fibrosis were identified. Alsopresent were lesions of severe emphysema and a 4-cm diameter neoplasm arising from the bronchus of the left upper lobe.
At microscopic examination, numerous interstitial collectionsof dust-laden macrophages were situated around the respiratory
bronchioles and along the adjacent alveolar septa. There wasa slight degree of fibrosis associated with the dust lesions andthe neoplasm was a poorly differentiated adenocarcinoma containing giant cell areas. Mineralogical analysis showed a large
amount of calcium Montmorillonite (Gibbs and Pooley 1994).
ZeoliteCasey et al. (1985) reported a patient living in the Nevada
desert who developed extensive pleural thickening and interstitial fibrous associated with the pulmonary deposition of Zeolite.
An open biopsy of the right lung and pleura was performed on the
52-year-old man. Mycobacterial and fungal cultures were negative. Histopathological evaluation established lesions of chronic

95

inflammation and fibrosis and presence of many fibrous andnonfibrous particles. The particles were analyzed by SEM andwere identified as aluminum silicates. The analytic pattern wascharacteristic of Zeolites. No asbestos fibers were found andexposure to these fibers was unlikely.
Zirconium Silicate
A nonsmoking 25-year-old woman developed a worsening
dry cough and dyspnea after 3.5 years as a tile sorter and glazer.
The woman had a history of atopic dermatitis and at age 13 developed pneumonia. An open lung biopsy specimen had lesionsof a severe granulomatous interstitial pneumonia with mild fibrosis and numerous very small birefringent crystals around theterminal airways and occasionally in the granulomas. Pulmonary
particle analysis established a dust burden almost 100 times thenormal. The particles consisted mainly of clay minerals and Zirconium Silicate (Lippo et al. 1993).

SUMMARY
This report provides a review of the safety of Aluminum,
Calcium, Lithium Magnesium, Lithium Magnesium Sodium,
Magnesium Aluminum, Magnesium, Sodium Magnesium, andZirconium Silicates, Magnesium Trisilicate, Attapulgite,
Bentonite, Fuller’s Earth, Hectorite, Kaolin, Montmorillonite,
Pyrophyllite, and Zeolite. These ingredients are termed silicatesbecause they contain silicon, oxygen, and one or more metals.
Many silicates occur naturally and are mined; yet others are
made synthetically.
Typical cosmetic uses of silicates include abrasive, opacifying agent, viscosity-increasing agent, anticaking agent, emulsion
stabilizer, binder, and suspending agent. Clay silicates (silicatescontaining water in their structure) primarily function as adsorbents, opacifiers, and viscosity-increasing agents. Pyrophyllite
is also used as a colorant. Current concentrations of use range
from as low as 0.01% for Zeolite to a high of 84% for Kaolin.
Some ingredients with no uses reported to FDA in 1998 havecurrent concentrations of use reported by the industry, so it isassumed they are in use.
Aluminum Silicate is approved as an indirect food additive in
the Code of Federal Regulations (21 CFR 177.2600 and 21 CFR
177.1200). VEEGUM, a tradename for Magnesium Aluminum
Silicate, has been designated by the FDA as a raw material withthe following number: FD CRMCS no. R0010045 and has anindividual Chemical Abstract Registry number, 12199-37-0. According to the European Cosmetic Directive (EU reference no.
391 Annex II), zirconium and its compounds are listed undersubstances that must not form part of the composition of cosmetic products, with the exception of complexes in Annex III,Part I. IARC has ruled Attapulgite fibers >5 µm as group 2B,
possibly carcinogenic to humans, and fibers <5 µm as group 3,
not classified as to their carcinogenicity to humans (IARC
1997). Bentonite is considered GRAS as a direct food additive(21 CFR 184.1155). Kaolin is considered GRAS as an indirect

Distributed for Comment Only -- Do Not Cite or Quote

96

COSMETIC INGREDIENT REVIEW

food additive (21 CFR 186.1256). Pyrophyllite is listed as anaturally occurring color additive in the Code of Federal Regulations (21 CFR 73.1400). The natural Zeolites (Clinoptilolite,
Phillipsite, Mordenite, Nonfibrous Japanese Zeolite) and synthetic Zeolites cannot be classified as to their carcinogenicity tohumans (group 3) according to IARC (1997). Calcium Silicate,
Magnesium Aluminum Silicate, Magnesium Trisilicate, Attapulgite, Hectorite, and Kaolin are all used in over-the-counterproducts.
Hectorite and Montmorillonite catalyzed glycine anddiglycine oligomerization reactions; oligomers were formed by
self-condensation of both purines and pyrimidines in the presence of Montmorillonite treated with Na+ . Under UV light,
adenosine monophosphate molecules were absorbed onto
Kaolin and the products were hydrolyzed by phosphodiesterase.
All silicates have the great ability to absorb, especially theclays. Reports describe drugs, bacteria, viruses, and toxins absorbed to clays due to the physical structure of clays and theircationic nature.
No statistically significant absorption of aluminum and elevated levels of silicon were recorded in assayed plasma samples of dogs given Magnesium Trisilicate and Zeolite orally.
The urinary excretion of silica was 5.2% in males given 20 g
of Magnesium Trisilicate. Ten percent Bentonite in the diets ofrats overcame T-2 toxicosis completely. Various Zeolites wereadded to the diets of pigs. No adverse effects were noted by the
supplementation.
A sample of Aluminum Silicate was toxic to pulmonary
alveolar macrophages and LDH activity and β-GAL release
were increased. Aluminum Silicate had relatively no effect on
the hemolysis of rat RBCs. Synthetic Calcium Silicate samples
and higher concentrations of Calcium Silicate caused increased
hemolysis of human RBCs; a greater fibrous character of Calcium Silicate samples caused increased LDH and β-GAL release. Many clays (Attapulgite, Bentonite, Hectorite, Kaolin,
Montmorillonite, Pyrophyllite, and Zeolite) demonstrated cytotoxicity to several macrophage type cell lines and have hemolytic
activity towards several species’ RBCs. 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 dosedependent effect on cytotoxicity or lysis was observed. Mostmineral samples were not 100% pure and many samples alreadycontained toxic dusts or minerals like quartz or cristobalite.
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 g/kg
in mice; Hectorite, >5 g/kg in rats; Kaolin, 149 g/kg in rats
(death due to bowel obstruction); 15 natural Zeolites, 10 g/kg
in rats. In short-term oral toxicity studies, no adverse effects
were seen in mice or rabbits dosed up to 5 g/kg Magnesium
Aluminum Silicate; beagle dogs and rats fed Aluminum Silicate
had no renal lesions. Dogs and rats fed Magnesium Trisilicate
for 4 weeks had polydypsia and polyuria, and all dogs had renal

cortical lesions. Guinea pigs had renal lesions after 4 monthsof drinking Magnesium Trisilicate in their tap water. Rats fed
10% Magnesium Aluminum Silicate had slightly elevated silicon levels of the spleen and dogs and rats fed 10% VEEGUM
had no negative responses in 90-day feeding studies. No lesions
were found in rats dosed up to 1000 mg/kg for 104 weeks.
The following results are from acute parenteral injection studies. Intratracheal injections of Aluminum Silicate caused lesions
in a dose-dependent manner and the intrapleural injections offour different Aluminum Silicate samples all resulted in lesions.
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. Subcutaneous injection into the oral mucosa andinto 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. Attapulgite was injected intraperitoneally, intrapleurally, and intratracheally in various studies. Most studies reported that lesions
and mesotheliomas were dependent on fiber length. Samples
with a longer length caused greater numbers of mesotheliomas.
Subplantar injections of Bentonite caused granulomas. Intratracheal injections of Bentonite and group C Streptococcus species
caused an 85% mortality compared to a 5% control mortality
in mice; another intratracheal injection caused loose reticulin
fibrils with no collagen. Kaolin injected with the Streptococcus
species caused statistically significant but modest mortality inmice. In a series of intrapleural injections, Kaolin was used as anegative control. Heat treated Montmorillonite dosed to rats bymeans of intratracheal instillation was restricted to alveoli within
and adjacent to alveolar ducts. Minor inflammatory reactions,but no lesions, were found in rats given intratracheal injections ofClinoptilolite, and intraperitoneal injections of Mordenite, Synthetic Zeolite 4A, and synthetic Zeolite MS5A (one mesothelioma was seen in rats given MS4A). An intrapleural injectionof Nonfibrous Japanese Zeolite caused two mesotheliomas inrats.
Small primary neoplastic lesions were found in two rats exposed to a Calcium Silicate sample in an inhalation chamber.
The mass of silicate measured in the lungs ranged from 0.1 to
0.8 mg. Lebrija and Leichester Attapulgite 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, respectively.
Both samples contained long fibers. Moderate to extensive respiratory disease was noted in rats chronically exposed to Synthetic
Zeolite A by inhalation methods.
The acute dermal LD50 was >3.5 g/kg for rabbits exposed
to VEEGUM. 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 ofthese studies. Sodium Magnesium Silicate (4%) had no primaryskin irritation in rabbits and had no cumulative skin irritation inDistributed for Comment Only -- Do Not Cite or Quote
SILICATES

guinea pigs. Hectorite was nonirritating to the skin of rabbits in
a Draize primary skin irritation study.
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. Bentonite caused severe iritis after injection into the anterior chamber of the eyes ofrabbits. When injected intralamellarly, widespread corneal infiltrates and retrocorneal membranes were recorded. In a primaryeye irritation study in rabbits, Hectorite was moderately irritating without washing and practically nonirritating to the eye witha washout. Rats tolerated a single dose of Zeolite A without any
adverse reaction in the eye.
Calcium Silicate (250 to 1600 mg/kg) had no discernible
effect on nidation or on maternal or fetal survival in rabbits.
Magnesium Aluminum Silicate (6000 mg/kg) had neither a teratogenic nor adverse effects on the mouse fetus. Female rats
receiving a 20% Kaolin diet exhibited maternal anemia but nosignificant reduction in birth weight of the pups was recorded.
Type A Zeolite produced no adverse effects on the dam, embryo, or fetus in either rats or rabbits at any dose level (74 or
1600 mg/kg). Clinoptilolite had no effect on female rat reproductive performance.
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. A subacute dose of 150 mg/kg of Calcium
Silicate produced 3% breaks in bone marrow cells arrested inc-metaphase. In a metaphase spread of bone marrow cells, Calcium Silicate produced no significant increase in the numberof aberrations compared to controls and in a dominant lethal
assay did not induce any dominant lethal mutations. In theS. typhimurium LT2 spot test (TA98, TA100, TA1535, TA1537,
and TA1538) with or without metabolic activation, Magnesium
Aluminum Silicate and Hectorite were found nonmutagenic.
In primary hepatocyte cultures, the addition of Attapulgite hadno significant unscheduled DNA synthesis (UDS) response or
modulated response to AAF (a positive control); Attapulgite at
10 µg/cm2 caused significant increases in UDS in rat pleural
mesothelial cells. Zeolite particles (<10 µm) produced statistically significant increase in the percentage of aberrant metaphases, mostly chromatid breaks.
Applications of 2 g of VEEGUM made to the skin of two
humans daily for 1 week caused no effects.
Occupational exposure to mineral dusts has been studied extensively. Fibrosis and pneumoconiosis has been documented inworkers involved in the mining and processing of Aluminum
Silicate, Calcium Silicate, Zirconium Silicate, Fuller’s Earth,Kaolin, Montmorillonite, Pyrophyllite, and Zeolite.

DISCUSSION
The CIR Expert Panel determined that the data provided inthis report are sufficient to assess the safety of the tested ingredients: Aluminum Silicate, Calcium Silicate, Magnesium Alu-

97

minum 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. The Panel did note a concern about inhalation of these ingredients due to reported casesof pneumoconiosis and fibrosis in humans and pulmonary lesions in animals. However, extensive pulmonary damage in humans was the result of direct occupational inhalation of the dusts
and lesions seen in animals were affected by particle size, fiber
length, and concentration. The Panel recognizes that most of theformulations are not respirable and of the preparations that are
respirable, the concentration of the ingredient is very low. Evenso, the Panel considered that any spray containing these solids
should be formulated to minimize their inhalation.
Note: The cosmetic ingredient, Talc, is a hydrated magnesium silicate with the chemical composition of Mg3 Si4 O10 (OH)2 .
Talc occurs in various forms and has a unique crystalline structure which differs from ingredients addressed in this safety assessment. Talc is not included in this report.
CONCLUSIONThe CIR Expert Panel concludes that 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 are safe as used in cosmetic products.
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Memorandum

TO:

Bart Heldreth, Ph.D.
Executive Director - Cosmetic Ingredient Review

FROM:

Carol Eisenmann, Ph.D.
Personal Care Products Council

DATE:

March 30, 2022

SUBJECT:

Clay

Argile du Velay. 2021. Technical data sheet Velay Green Clay.
Anonymous. 2022. Summary information French Velay Green Clay (ingredient tested as described in
the Agile du Velay technical data sheet for Velay Green Clay).

Updated on 22/12/2021 – Version 19
Distributed for Comment Only -- Do Not Cite or Quote

COSMETIC INGREDIENT
In compliance with Regulation (EC) n°1223/2009

INGREDIENT INFORMATIONS
Trade name :Reference :Composition :Origin of the ingredient :Manufacturer :HSCode :Velay Green clay
CosGREENTM
100% natural mineral productFranceArgile du Velay, ZA de Nolhac
43350 Saint-Paulien
2508400000

Description of the manufacturing process:
The Velay green clay is mechanically refined, without any chemical process. Bacteria areeliminated by a sophisticated dehydration process. Powder grains are then sorted thanks to an
innovative process of selection by induction.

* The INCI composition above includes a portion of non-clay minerals.

This clay is guaranteed without quartz.

INGREDIENT SPECIFICATIONSPHYSICO-CHEMICAL ANALYSIS
AspectOdor
Humidity

Beige green powder
None
< 8%

(Humidimeter METTLER TOLEDO)

pH

Between 8 and 9(Method : NF EN ISO 787-9 & T31-235)

Grain size
(Granulometer Mastersizer 2000 Malvern)

Oil absorption
Water absorption

I5 :80% < 5µm 100% < 10µm
Ultra-ventilated : 90% < 20µm 100% < 40µm
Surfine :90% < 77µm 100% < 100µm
I750 :
90% < 750µm 100% < 1100µm
Average of 58% ± 10 depending on grain size
Average of 80% ± 10 depending on grain size

SAS au capital de 1 000 000 € - N°TVA : FR25 380171975
SIRET 380 171 975 00028 - APE 2399Z - RC LE PUY EN VELAY – France

www.argileduvelay.com

Updated on 22/12/2021 – Version 19
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MICROBIOLOGICAL ANALYSIS
Ingredient available in category 1 or 2 (According to the ISO 17 516). Specifications

Category 1

Specifications
Category 2

Total aerobic mesophilic microorganisms (Aerobic
mesophilic bacteria DGAT (NF EN ISO 21149) andYeasts and molds DMLT (NF EN ISO 16212))< 100 CFU/g a< 1 000 CFU/g b

Pseudomonas Aeruginosa (NF EN ISO 21148 and 22717)
Staphylococcus Aureus (NF EN ISO 21148 and 22718)
Candida Albican(NF EN ISO 21148 and 18416)
Escherichia Coli (NF EN ISO 21148 and 21150)

NONE
NONE
NONE
NONE

NONE
NONE
NONE
NONE

Due to the inherent variability of the enumeration method and according to the USP chap 61 or EP chap 2.6.12, results are out of specs
a > 200 CFU/gb > 2 000 CFU/g
if:

Quotes are by default in category 2. Category 1 (100% natural heat treatment) is available on request and will
be clearly identified on the quote.

REGULATORY INFORMATION
Natural cosmetic ingredient in accordance with the ISO 16128-1 / 2016 standards: "Natural ingredientderived from an inorganic substance, naturally occurring in nature, having its own chemical formula and acoherent set of physical properties. "EUROPEAN COSMETIC REGULATION 1223/2009 OF NOVEMBER 30th, 2009
The CosGREENTM is not included in the list of banned substances, ref: Annex II Regulation 1223/2009 –Cosmetics products - of the European Parliament and Council, November 30th, 2009. This product can beused in the manufacturing of cosmetics products.

COSMOS/ECOCERTThe CosGREENTM is COSMOS and ECOCERT certified as a cosmetic ingredient authorized in the
manufacturing of natural and organic cosmetics. www.cosmos-standard-rm.org/.

IRRADIATIONThe CosGREENTM does not undergo any irradiation treatment during its manufacturing process.

REACH
This reference is exempted- Annex V, Chapter 7 of the European Regulation 1907/2006 (REACH) - (substancepresent in nature / substance not chemically modified). No chemical substance, PBT substance (bioaccumulative and toxic substances) or any vPvB substances (very persistent and very bio accumulative
substance of concern) are in contact with the product during the manufacturing process.

CMR
CosGREENTM is not classified as CMR (carcinogenic, mutagenic and reprotoxic substances) and no CMR
substances are in contact or added during the manufacturing process.

SOLVENTThe CosGREENTM is from natural origin. No chemical and no solvent are in contact or added during the
manufacturing process. It therefore doesn’t contain solvent residues.

ALLERGENSThe CosGREENTM naturally doesn’t contain allergens, and no substances are in contact or added during the
manufacturing process. It does not contain any allergenic substances listed in Annex III of Regulation
1223/2009 - Cosmetics products - of the European Parliament and of Council of November 30th, 2009.

SAS au capital de 1 000 000 € - N°TVA : FR25 380171975
SIRET 380 171 975 00028 - APE 2399Z - RC LE PUY EN VELAY – France

www.argileduvelay.com

Updated on 22/12/2021 – Version 19
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GMO
The CosGREENTM is a natural mineral and doesn’t contain substances of plant origin. No GMO substances
are in contact or added during the manufacturing process.

ESB/TSEThe CosGREENTM is a natural mineral and doesn’t contain animal or human substances, it is not in contact
with this type of substances during the manufacturing process. It can not therefore cause transmissible
spongiform encephalopathy (ESB / TSE).

SVHCThe CosGREENTM is a 100% natural mineral. No preoccupating or really preoccupating substances (SVHC)
and no preoccupating or really preoccupating chemicals substances defined by the European chemicals
agency are used during the manufacturing process.

ANIMAL TESTING
No animal testing has been carried out since 2009, in accordance with Regulation 1223/2009 of theEuropean Parliament and Council of November 30th, 2009 on cosmetic products.

VEGETARIAN / VEGAN
No ingredients from animal origin are in contact or added in the manufacturing process.

HALAL
General guidelines of the FAO (Food and Agriculture Organization of the United Nations) for the use of"Halal" N ° CAC / GL 24-1997 are excluding following products:* Product of animal origin* Product of vegetable origin* Alcoholic and / or intoxicating and dangerous drinks* Food additives obtained from what is listed in points 1., 2. and 3.

The CosGREENTM naturally does not contain any prohibited substances listed above. No substances are incontact or added during the manufacturing process, so this reference may be eligible to the Halalcertification.

CASHERThe CosGREENTM is a 100% natural mineral. No additives have been added during the manufacturing
process, this mineral can be eligible to get the Casher certification.

NANOMATERIALSRegulation 1223/2009 of the European Parliament and of Council November 30th, 2009 on cosmetic
products defines 'nanomaterials' as: ‘insoluble, bio-persistent and intentionally produced with one or more
external dimensions at the level of 1 to 100nm’. The CosGREENTM is not intentionally produced at thenanoparticle scale and therefore complies with Regulation 1223/2009 of the European Parliament and of
Council November 30th, 2009 on cosmetic products. And so, CosGREENTM does not need to be annually
declared to the ANSES (decree 2012-232 of 17th, 2012).

CALIFORNIA PROPOSITION 65
Not listed.

NATURALITY INDEX“A natural ingredient is made from organic substances naturally in Earth having its own chemicals formulaand its own physical properties”. According to the ISO 16128, clays’ characteristics are as following:* Natural index = 1* Natural origin index = 1* Biological index = 0* Biological origin index = 0

SAS au capital de 1 000 000 € - N°TVA : FR25 380171975
SIRET 380 171 975 00028 - APE 2399Z - RC LE PUY EN VELAY – France

www.argileduvelay.com

Updated on 22/12/2021 – Version 19
Distributed for Comment Only -- Do Not Cite or Quote

DIOXIN AND PCB
Results are near zero.

HEAVY METALSThe CosGREENTM is a mineral naturally present in nature, therefore it can contain traces of heavy metals(ppm), tolerated by the European regulation because technically unavoidable. Internal method, sample’s
mineralization with nitric acid at 5% (EN 15510), measurement carried out by using ICP-OES spectrometry(9820 SHIMAZU).
Antimony Sb< 0.5 ppm
Tin Sn< 0.5 ppm

Arsenic As Cadmium Cd< 17 ppm< 0.5 ppm
Mercury Hg Nickel Ni< 0.05 ppm < 20 ppm

Cobalt Co< 7 ppm
Lead Pb< 20 ppm

TOXICOLOGICAL AND ECOLOGICAL INFORMATION
For this section, please refer to SDS001.

EXPIRATION, PACKAGING, STORAGE
Microbiological expiry date depends on the category:Category 1 : 6 months after leaving our warehouse
Category 2 : 18 months after leaving our warehouse
After this period of time, this parameter must be rechecked.

This product is packed in paperbag or BIG BAG.
Store in a dry, well-ventilated and free from any microbiological contamination place.

VISA :BERNARD Emmanuel - President

SAS au capital de 1 000 000 € - N°TVA : FR25 380171975
SIRET 380 171 975 00028 - APE 2399Z - RC LE PUY EN VELAY – France

www.argileduvelay.com

Distributed for Comment Only -- Do Not Cite or Quote

March 2022
OCDE N°

402

403

STUDY TITLE

SUMMARIESPRODUCTTESTED

SPECIESRESULTS

CLASSIFICATION

Date

Acute dermal toxicity

10 per cent of the body surface area was clipped 24
hours prior to the dermal application of the test
substance. Group 1 served as the control treated with
0,2ml of distilled water. Group 2 treated with 2000mg
of French Velay Green Clay per kg body weightmoistened with 0,2ml of distilled water by single
dermal application and observed for a period of 14
days.

DURATIO
N OF
STUDY

French Velay
Green ClayRat

14 days of
study.

DL50>2000mg/kg
No mortality and toxic sign were observed at this doselevel of clay treatment.

Category 5 => non
toxic

June 2008

Acute inhalation
toxicity study

Group 1 were exposed to air passed through inert bed
material (iron grit) and served as the control. Group 2
were exposed to the maximum achievable breathingzone concentration (3.856 mg/L air) of French Velay
Green Clay. Rats of either group were exposed during
4 hours followed by observation for a period of 14
days.

Rat

Exposure: 4
hours
during 14
days ofstudy.

Category 5 or
unclassified =>nontoxic

July 2008

Rabbit72 hours
after
releasingthesubstance

The mean dermal irritation scores of erythema (0;00) andoedema (0.00) following 24, 48 and 72 hours, notsignificant for all the rabbits. Not classified as skin irritant.

Unclassified =>Non irritating

June 2008

Rabbit72 hours
after
instillation

Treated eyes of all rabbits appeared as normal at 72
hours post installation of French Velay Green Clay. Not
classified as eye irritant.

Unclassified =>Non irritating

June 2008

Guinea pig (10controls [5/sex] ;20 treated[10/sex]

48 hours
after
releasingthesubstance

Visual observation of the skin following challenge
exposure didn't reveal any positive skin response at 24 or
48h post patch removal. No clinical signs related totreatment were observed during the course of the study.

Negative

July 2008

404

Acute dermal
irritation study

405

Acute eye irritation
study

406

Skin sensitisation
study

French Velay
Green ClayA patch with 500mg of French Velay Green Claymoistened with 0,5ml of distilled water was applied tothe intact skin of rabbits. The treated and the control
sites were covered with a gauze patch and secured at
French Velay
the margins by non-irritating tape for a period of 4
Green Clayhours. At the end of the exposure period, the residual
test substance was removed with cotton soaked in
distilled water. The skin reactions were observed andscored at 1, 24, 48 and 72 hours post patch removal.
100mg of French Velay Green Clay was instilled into
one eye of each rabbit. The contralateral eye served as
French Velay
the control and was instilled with 0,1ml of normal
Green Claysaline. Observations were made after 1, 24, 48 and 72
hours post instillation.
5% (w/v) concentration of French Velay Green Clay in
distilled water in intradermal injection during
French Velay
induction exposure on day 0. On day 7, 100mg ofGreen Clay
French Velay Green Clay distilled in 0,2ml of distilledwater for topical application during induction.

DL50 2000 and 5000 mg/kg and CL50 =3,856mg/L
No mortality and toxic sign were observed at this doselevel at the maximum achievable breathing zone
concentration (3.856 mg/L air) of French Velay Green
Clay.

DL50=5000mg/kg
423

Acute oral toxicity
study

Single oral dosage : 2000mg of French Velay Green
Clay per kg body weight in distilled water.

French Velay
Green ClayRat

14 days of
study

Category 5 or
No mortality and toxic sign were observed at this dose
unclassified => nonlevel. Visceral examination did not reveal any lesion of
toxic
pathological significance except uterine distension in one
rat, considered unrelated with the clay treatment.

June 2008

March 2022

471

Bacterial reverse
mutation test of
French Velay Green
Clay using Salmonella
typhimurium

473

In-vitro mammalianchromosome
aberration test

N/A

Ex-vitro study:
bioavailability bytranscutaneous
passage in a humanskin model of heavy
metals naturally
present in threeclayed pastes

Distributed for Comment Only -- Do Not Cite or Quote

Study performed to evaluate mutagenic activity ofFrench Velay Green Clay by bacterial reverse mutation
test, using five histidine deficient mutant tester strains
French Velay
of Salmonella typhimurium. 5000µg of French Velay
Green Clay
Green Clay was tested in the mutagenicity test both in
the absence and presence of the metabolic activation
system (5% v/v S9 mix) for all the tester strains.
2 TESTS : metabolic activation 2% and 4% v/v S9).
CHO-K1 cell cultures were exposed to the French
Velay Green Clay at concentrations of 156.25, 312.5, French Velay
625, 1250, 2500 and 5000 µg/ml culture media both in Green Clay
the absence and presence of metabolic activation for aperiod of 4 hours.
The aim of the study is to evaluate quantities of lead,arsenic, nickel, barium, chromium andvanadium contained in clayed pastes of French Velay
Green Clay, White Montmorillonite andKaolin, to determine heavy metals’ bio-availability bytranscutaneous passage.
Entire human skin fragments of a 62 years old female
donator have been used to handle thisstudy.
Fragments have been put on Franz cells by applying
skin pieces on the top of the receiving
French Velay
compartment stratum corneum.
Green ClayFor each tested product, the tested product ( 150/Whitegrams), diffusion liquids (collected in thereceiving compartment of the Franz cell at the end of Montmorillo
nite/
the incubation) and the storage liquids (Kaolincollected after 24 skin fragments’ macerating hours
after the incubation) have been sent to
EUROFINS laboratory to evaluate the quantity of
vanadium, lead, arsenic, barium, nickel andchromium.
Before making dosages, samples of bulk clays
undergone a preparation by samples’ digestion
with nitric acid by using micro-waves at 235° Celsius
degrees.
Samples corresponding of diffusion and storage liquids
didn’t undergone any preparation by
micro-waves’ digestion before doing dosages.

Salmonella
typhimurium
trainsIn vitro test

Ex vitro test

48 hours

From results of this study, it is concluded that French
Velay Green Clay is non-mutagenic to all five Salmonella
typhimurium tester strains viz. , TA1537, TA1535, TA98,
TA100 and TA102 both in absence and presence of
metabolic activation.

Negative

September
2011

21 hours of
exposure

From results of this study, it is concluded that the French
Velay Green Clay didn't show potential to induce
chromosomal aberrations both in the absence nad
presence (2 and 4% v/v S9) of metabolic activation
system.

Negative

September
2011

48 hours

From results of this study, it is concluded that heavy
metals’ traces in clayed pastes are not penetrating the
cutaneous tissue.
Indeed, no detectable quantity of heavy metals has beenfound during studies made on the“diffusion” (none transcutaneous passage has been put inemphasis), nor “storage” (nodetectable heavy metals’ traces have been detected in
the cutaneous tissue).

N/A

October 2019

March 2022

N/A

Ex-vitro study:
bioavailability bytranscutaneous
passage in a humanskin model ofaluminium naturally
present in threeclayed pastes

Distributed for Comment Only -- Do Not Cite or Quote

The aim of the study is to evaluate quantities of lead,arsenic, nickel, barium, chromium andvanadium contained in clayed pastes of French Velay
Green Clay, White Montmorillonite andKaolin, to determine aluminium bio-availability bytranscutaneous passage.
Entire human skin fragments of a 62 years old female
donator have been used to handle thisstudy.
Fragments have been put on Franz cells by applying
skin pieces on the top of the receiving
compartment stratum corneum.
For each tested product, the tested product ( 150
grams), diffusion liquids (collected in thereceiving compartment of the Franz cell at the end of
the incubation) and the storage liquids (collected after 24 skin fragments’ macerating hours
after the incubation) have been sent to
EUROFINS laboratory to evaluate the quantity ofaluminium.
Before making dosages, samples of bulk clays
undergone a preparation by samples’ digestion
with nitric acid by using micro-waves at 235° Celsius
degrees.
Samples corresponding of diffusion and storage liquids
didn’t undergone any preparation by
micro-waves’ digestion before doing dosages.

French Velay
Green Clay
/WhiteMontmorillo
nite/
KaolinEx vitro test

48 hours

From results of this study, it is concluded that heavy
metals’ tracesin clayed pastes are not penetrating the cutaneous
tissue.
Indeed, no detectable quantity of heavy metals has beenfound during studies made on the “diffusion” (nonetranscutaneous passage has been put in emphasis), nor“storage” (no detectable heavy metals’ traces have been
detected in the cutaneous tissue).

N/A

February 2021

March 2022

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French Velay Green Clay surfine (77µm)

March 2022

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French Velay Green Clay ultra ventilated (20µm)

Distributed for Comment Only -- Do Not Cite or Quote

Memorandum

TO:

Bart Heldreth, Ph.D.
Executive Director - Cosmetic Ingredient Review

FROM:

Carol Eisenmann, Ph.D.
Personal Care Products Council

DATE:

April 4, 2022

SUBJECT:

Bentonite and Kaolin

Anonymous. 2018. Clinical safety evaluation repeated insult patch test of a clay mask containing
3.8% Bentonite.
Anonymous. 2016. Clinical safety evaluation repeated insult patch test of a lip product containing
14.498% Kaolin.

Distributed for Comment Only -- Do Not Cite or Quote

Clay mask containing 3.8%
BentoniteDistributed for Comment Only -- Do Not Cite or Quote

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lip product containing 14.498% Kaolin

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Memorandum

TO:

Bart Heldreth, Ph.D.
Executive Director - Cosmetic Ingredient Review

FROM:

Carol Eisenmann, Ph.D.
Personal Care Products Council

DATE:

April 25, 2022

SUBJECT:

Bentonite and Kaolin

Anonymous. 2019. Repeated insult patch test (product contains 3.5% Bentonite).
Anonymous. 2017. Clinical use test results of a 5 in 1 facial cleanser (containing 2% Bentonite and
2% Kaolin).
Anonymous. 2012. A 14-day cumulative irritation assay (product contains 1.75% Bentonite).
Anonymous. 2017. Photoallergy study (product contains 1.75% Bentonite).
Anonymous. 2003. Human patch test (mask contains 8% Bentonite).

Distributed for Comment Only -- Do Not Cite or Quote

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STUDY REF. #
TO:

File

FROM:
DATE:

April 20, 2017

SUBJECT: Clinical Use Test Results of

5-in-1 Facial Cleanser #SUMMARY

contains 2% Bentonite and 2% Kaolin

5-in-1 Facial Cleanser #was tested via a four-week Dermatologistsupervised Clinical Use study. The study was a single-blind baseline controlled monadic design with
, a Board Certified Dermatologist, as the principal investigators. Subjects were
instructed to use the product to use the product in the following ways for three weeks: daily in themorning as a facial cleanser, twice weekly in the evening as an exfoliating scrub, twice weekly in theevening as a purifying mask and three times weekly in the evening as a facial cleanser.
The Dermatologist did not observe any visible clinical irritation specifically related to use
5-in-1 Facial Cleanser.
Eight (16%) subjects reported perceived discomfort and/or irritation, including burning/stinging
and/or redness/dryness, while using the Cleanser. The occurrence of response was spread over all thevarious applications for the product, i.e. facial cleanser, purifying mask and scrub.
There were five reports of visible irritation, i.e. redness/visible dryness, during 5-in-1 use; someof these were also accompanied by sensations of discomfort. All of these were slight inintensity and none were corroborated by Dermatologist evaluation. Additionally, five subjects
reported sensations of discomfort, i.e. burning/tingling/itching, during 5-in-1 use; some of thesewere also accompanied by perceived visible irritation. These sensations ranged from slight tomoderate in intensity and the majority of these persisted for a duration of five minutes or less.
Six of the eight reported responses were either not considered to be specifically related to use of the
5-in-1 Cleanser due to subject-acknowledged personal history of similar response, resolving
spontaneously without recurrence despite continued product application or being limited to a small
section of the overall use area. The remaining two subjects experienced responses that continued
throughout the study period, however neither subject felt that their response was of sufficient intensity
to warrant discontinuation of product use at any time.
The level of perceived response in this study is well within the parameters for product acceptability
therefore, these responses were not considered to impact the overall safety in use of the 5-in-1
Cleanser.
The 5-in-1 Cleanser is considered to be acceptable for use. A claim of “suitable for sensitive skin” issupported by the results of this study.
1

Distributed for Comment Only -- Do Not Cite or Quote

STUDY OBJECTIVES•

To determine the potential of
5-in-1 Facial Cleanser #to evokeclinical irritation and/or subject-perceived discomfort/irritation when used under consumer use
conditions.

•

To provide support for a claim of “suitable for sensitive skin” forCleanser.

5-in-1 Facial

TEST DESIGN
A total of fifty (50) individuals completed this four-week, Dermatologist-supervised Clinical Use
Test. In order to support the claim of “suitable for sensitive skin” thirty-seven of these individuals(74%) had Testing Center-assessed sensitive skin while the remaining thirteen were considered to be“non-sensitive”. Dermatologist-assessed facial exams were conducted at the baseline, two-weekinterim and final visits. Test design and Criteria for Testing Center Assessed Skin Sensitivity arepresented in Appendix I. Product identification and product use instructions are presented inAppendix II. Subject demographics are listed in the study file.

STUDY DATESMarch 8, 2016 - April 5, 2016

RESULTS: DERMATOLOGIST-ASSESSED VISIBLE IRRITATIONThe Dermatologist did not observe any product related irritation. A tabulation of Dermatologistassessed clinical changes may be found in Appendix III.
The Dermatologist observed clinical changes mainly in scaling and conditions of acne, including
papules and pustules. The level of positive changes in conditions of acne was significantly higher
than the level of negative changes in the same conditions. Slightly more subjects were observed tohave negative versus positive changes in scaling, however all changes observed during the study
period were determined to within the parameters for normally occurring and/or seasonally related skinconditions.

PERCEIVED IRRITATION
Eight subjects (16%) reported experiencing subjective discomfort/irritation during the study period.
No follow-up testing was conducted.
Four subjects experienced subject discomfort and/or irritation that was not considered to be
specifically related to the 5-in-1 Cleanser as the subjects self-acknowledged a personal history of2Distributed for Comment Only -- Do Not Cite or Quotesimilar response to other facial cleansing products. These responses included burning/itching withredness and/or dryness; the visible irritation was not corroborated by the Dermatologist.
One subject experienced an episodic burning sensation that resolved spontaneously without
recurrence despite continued product use.
One subject reported episodic redness that was limited to a small section, i.e. nose, of the overall use
area.
The remaining two subjects experienced responses that continued throughout the study period; one
subject experienced moderate tingling with each product use while the other reported redness only
following use as a mask and scrub. Neither subject felt that their response was of sufficient intensity
to warrant discontinuation of product use at any time.
This level of perceived response is well within the parameters for product acceptability therefore,
these responses were not considered to impact the overall safety in use of the 5-in-1 Cleanser.
Detailed Case Chronologies may be found in Appendix IV.

CONCLUSION
5-in-1 Facial Cleanser #exhibited acceptable results. The results of thisstudy will provide support for a claim of “suitable for sensitive skin”.

3Distributed for Comment Only -- Do Not Cite or Quote

Prepared By:
Associate Clinical Scientist

Approved By:, Pharm.D., PhD
Senior Toxicolgoist

Approved By:, M.D.
Consultant Dermatologist

4Distributed for Comment Only -- Do Not Cite or Quote

APPENDIX ITEST DESIGN
Fifty (50) subjects completed a four-week, Dermatologist-supervised clinical use test. The panel was
conducted as single-blind, baseline controlled monadic design evaluation.
The test product was supplied to all of the subjects for the 4-week evaluation period.
Test products were packaged in appropriate tubes and labeled with product type, i.e. FACIAL
CLEANSER/SCRUB/MASK. Products were supplied to subjects with use instructions.
Dermatologist-assessed facial exams were conducted initially, at the two-week interim visit and uponcompletion of the study. Questionnaires seeking subject perceived problems were completed by the
subjects at the end of each two-week study period.

CRITERIA FOR DETERMINING TESTING CENTER-ASSESSED SENSITIVITYA SENSITIVES: Must have at least 3 characteristics from List #1
B SENSITIVES: Must have 2 characteristics from List #1 and at least 2 characteristics from List #2.
C SENSITIVES: Must have 2 characteristics from List #1 and at least 1 characteristic from List #2.
(NOTE: All data for parameters designated as self-assessed or self-acknowledged is obtained fromquestionnaires completed by subjects. Testing Center Assessed data was obtained via
facial screening exams conducted by Testing Center personnel.)
LIST #1
Self-Assessed Very Sensitive / Sensitive Skin
Self-Assessed Sun Sensitivity
Allergies

Flusher/Blusher
Eczema History
Testing Center-Assessed Rosacea
Testing Center-Assessed Seborrheic Dermatitis- (i.e. Fitzpatrick Types I, II)- (self-acknowledged - including but notlimited to pollen, dust, drugs, foods –ranging from one to multiple)- (self-acknowledged)- (self-acknowledged)- (based upon evaluation screening by
Testing Center personnel)- (based upon evaluation screening by
Testing Center personnel)

LIST #2
Self-Assessed Skin Type of Normal to Dry or Dry
Blonde/Red Hair Color- (self-acknowledged)
Non-Soap User
- (self-acknowledged user of facial
cleanser)
Testing Center-Assessed Telangiectasia- (based upon evaluation screening by
Testing Center Personnel)
Testing Center-Assessed Very Fair/Fair Complexion - (based upon evaluation screening by
Testing Center Personnel)
Testing Center-Assessed Freckling- (based upon evaluation screening by
Testing Center Personnel)
5Distributed for Comment Only -- Do Not Cite or Quote

APPENDIX II

USE INSTRUCTIONSFACIAL CLEANSER / SCRUB / MASKUSE THIS PRODUCT TWICE A DAY, MORNING AND EVENING !!
USE IN PLACE OF YOUR REGULAR METHOD OF WASHING YOUR FACE AND YOURREGULAR FACIAL SCRUB AND/OR MASKDAYTIME USE:
1. Use this Cleanser in the morning to cleanse your face.
2. Wet face and hands generously.
3. Gently massage over skin in circular motions to remove dirt and impurities, avoiding the eyearea.
4. Rinse well with warm water and gently pat dry.
5. Please continue to use your own regular facial moisturizer.
NIGHTTIME USE:
1. At night you will use this product three different ways.
2. TWICE A WEEK: Use the product as an EXFOLIATING CLEANSING SCRUB
a. Moisten hands and face.
b. Massage onto facial skin in circular motions for one (1) minute, avoiding the eye area.
c. Rinse clean with warm water.
3. TWICE A WEEK: Use the product as a DEEP PURIFYING CLEANSING MASK
a. Moisten face.
b. Spread a thin layer onto damp skin, avoiding the eye area.
c. Let dry for five (5) minutes.
d. Rinse thoroughly with warm water.
4. REMAINING NIGHTS OF THE WEEK: Use the product as directed under DAYTIME USE.
5. Please continue to use your own regular facial moisturizer.
NOTE: For external use only.
Keep out of reach of children.
Avoid use in the eye area. If contact occurs, rinse thoroughly with water. Do not rub.
REMEMBER:
1. Bring your product with you on the exam dates (March 22nd and April 5th).
2. This product is for your use only. Do not let other members of your family use it
3. Should any problems arise while using the product, please call theand ask for.

6

Distributed for Comment Only -- Do Not Cite or Quote

APPENDIX II (cont.)

Test:

5-in-1 Facial Cleanser
FORMULA #FACIAL CLEANSER / SCRUB / MASKAPPENDIX III
Total Tabulation of Clinical Changes
Dermatologist-Supervised
N=51*
#
25
25

# of subjects that exhibited a change**# of subjects that exhibited no change

Scaling
increased
decreased

Test
6
4

Erythemaincreased
decreased

0
1

Acne
increased
decreased

7
12

Papulesincreased
decreased

6
10

Pustulesincreased

1

%
50
50

7

Distributed for Comment Only -- Do Not Cite or Quotedecreased

2

Maculesincreased
decreased

0
1

Seborrheic Dermatitis
increased
decreased
*
**

2
1

- One subject dropped from the study due to non-product related reasons.
- Subjects may have exhibited more than one change.

APPENDIX IV
SUBJECT-PERCEIVED DISCOMFORT/IRRITATION

AG #7

Testing Center-Assessed Skin Sensitivity:
Self-Assessed Skin Sensitivity:
Self-Assessed Skin Type:
Facial Cleanser User:
Facial Scrub User:
Facial Moisturizer User:A
Sensitive
Normal to Oily
Dove / Bliss Foam Cleanser
None
Olay

CASE CHRONOLOGY
3/8/16reported to the Testing Center for her scheduled initial visit. She was given
5-in-1 Facial Cleanser to use twice a day, morning and evening, for four weeks.
Subjects were instructed to use the product to cleanse the face each morning. For
nighttime use, the subjects were instructed to use the product as a facial cleanser threenights, as an exfoliating cleansing scrub two nights, and as a deep purifying cleansing
mask on the remaining two nights each week. Subjects were allowed to continue use of
their own regular moisturizer.
She was Dermatologist-assessed as having mild central facial erythema, closed
comedones of the cheeks and rosacea.

3/22/16

returned to the Testing Center for her scheduled interim visit. She stated that,while using the product as a facial cleanser, she observed visible redness. The redness
occurred after rinse-off on the upper cheeks and persisted for a few minutes each time; it
was not accompanied by any sensations of discomfort. The subject also noted that,
8Distributed for Comment Only -- Do Not Cite or Quote

during the first two uses of the product as an exfoliating scrub, she experienced aburning sensation. The discomfort was slight in intensity and lasted for about one
minute each time.
She was Dermatologist-assessed as having pre-existing mild central facial erythema,closed comedones of the cheeks and rosacea. (no change)
Instructions: The subject was asked to continue using the product as instructed. She will contact theTesting Center if her response worsens. She will return to the Testing Center for herscheduled final visit.

4/5/15returned to the Testing Center for her scheduled final visit. She stated that, during
the final two weeks of product use as a facial cleanser, she had not experienced any
further episodes of redness. However, the subject noted that she did continue toexperience occasional episodes of burning when using the product as an exfoliatingscrub. The discomfort continued to be slight in intensity, lasting only about one minute
APPENDIX IV (cont.)
SUBJECT-PERCEIVED DISCOMFORT/IRRITATION

each time. The subject noted that she has experienced a similar response in the pastwhen using other facial scrub products.
The subject was Dermatologist-assessed as having papules of the cheeks with preexisting mild central facial erythema, closed comedones of the cheeks and rosacea.
Judgment: No follow-up testing was conducted. The subject’s response of redness with burning
was episodic in nature, resolving spontaneously without recurrence despite continued
product use. Her response of burning while using the product as an exfoliating scrub
was also episodic and transient in nature. Additionally, this response was notconsidered to be specifically related to use of the test product as the subject selfacknowledged a personal history of similar response when using other facial scrub
products. This response will not impact the overall safety in use of the 5-in-1 Facial
Cleanser.

9

Distributed for Comment Only -- Do Not Cite or Quote

APPENDIX IV (cont.)
SUBJECT-PERCEIVED DISCOMFORT/IRRITATION

BG #4

Testing Center-Assessed Skin Sensitivity:
Self-Assessed Skin Sensitivity:
Self-Assessed Skin Type:
Facial Cleanser User:
Facial Scrub User:
Facial Moisturizer User:A
Sensitive
Normal to Oily
Dove
None
Neutrogena

CASE CHRONOLOGY
3/8/16reported to the Testing Center for her scheduled initial visit. She was given
5-in-1 Facial Cleanser to use twice a day, morning and evening, for four weeks.
Subjects were instructed to use the product to cleanse the face each morning. For
nighttime use, the subjects were instructed to use the product as a facial cleanser threenights, as an exfoliating cleansing scrub two nights, and as a deep purifying cleansing
mask on the remaining two nights each week. Subjects were allowed to continue use of
their own regular moisturizer.
She was Dermatologist-assessed as having moderate central facial erythema, one papuleof the nose, seborrheic dermatitis of the brows and glabella, open pores and rosacea.

3/22/16

returned to the Testing Center for her scheduled interim visit. She stated that, while
using the product as an exfoliating scrub, she experienced soreness, with slight redness,on the sides of the nose and visible dryness/redness, accompanied by itching, on thechin. The sensation of “soreness”, with redness, occurred while using the product. The
10

Distributed for Comment Only -- Do Not Cite or Quoteslight dryness/redness, accompanied by mild itching, on the chin persisted for a coupleof hours after scrub use. The subject noted that she has experienced a similar responsein the past when using other facial cleansing scrubs.
She was Dermatologist-assessed as having seborrheic dermatitis of the sides of the nosewith pre-existing moderate central facial erythema, open pores and rosacea.
Instructions: The subject was asked to continue using the product as instructed. She will contact theTesting Center if her response worsens. She will return to the Testing Center for herscheduled final visit.
4/5/15returned to the Testing Center for her scheduled final visit. She stated that, during
the final two weeks of product use as an exfoliating scrub, she continued to experienced
soreness/redness on the sides of the nose during use with dryness/redness and itching on
the chin following use. BG noted that none of the irritation and/or discomfort had
worsened despite continued use of the product. The subject again noted that she has
experienced a similar response in the past when using other facial scrub products.
APPENDIX IV (cont.)
SUBJECT-PERCEIVED DISCOMFORT/IRRITATIONThe subject was Dermatologist-assessed as having pre-existing moderate central facial
erythema, one papule of the nose, open pores and rosacea.
Judgment: No follow-up testing was conducted. The subject’s responses of limited visible
irritation, i.e. sides of nose and chin, and accompanying mild discomfort was notconsidered to be specifically related to use of the test product as the subject selfacknowledged a personal history of similar response when using other facial scrub
products. This response will not impact the overall safety in use of the 5-in-1 Facial
Cleanser.

11

Distributed for Comment Only -- Do Not Cite or Quote

APPENDIX IV (cont.)
SUBJECT-PERCEIVED DISCOMFORT/IRRITATION

SH #33

Testing Center-Assessed Skin Sensitivity:
Self-Assessed Skin Sensitivity:
Self-Assessed Skin Type:
Facial Cleanser User:
Facial Scrub User:
Facial Moisturizer User:

B
NormalNormal to Dry
L’Oreal Rejuvenate
None
L’Oreal

CASE CHRONOLOGY
3/8/16reported to the Testing Center for her scheduled initial visit. She was given
5-in-1 Facial Cleanser to use twice a day, morning and evening, for four weeks.
Subjects were instructed to use the product to cleanse the face each morning. For
nighttime use, the subjects were instructed to use the product as a facial cleanser threenights, as an exfoliating cleansing scrub two nights, and as a deep purifying cleansing
mask on the remaining two nights each week. Subjects were allowed to continue use of
their own regular moisturizer.
She was Dermatologist-assessed as having moderate general erythema, closed
comedones of the forehead, actinic keratoses, telangiectasia and rosacea.

3/22/16

returned to the Testing Center for her scheduled interim visit. She stated that,during product use in general, she experienced dryness of the skin. SH noted that she
observed visible dryness, which was not accompanied by any sensations of discomfort.
The subject noted that the visible dryness was relieved by application of her own regularmoisturizer.
12

Distributed for Comment Only -- Do Not Cite or Quote

She was Dermatologist-assessed as having pre-existing moderate general erythema,closed comedones of the forehead, actinic keratoses, telangiectasia and rosacea. (nochange)Instructions: The subject was asked to continue using the product as instructed. She will contact theTesting Center if her response worsens. She will return to the Testing Center for herscheduled final visit.
4/5/15returned to the Testing Center for her scheduled final visit. She stated that, during
the final two weeks of general product use, she continued to observe visible dryness on
the face. The dryness was not accompanied by any sensations of discomfort and was
relieved by use of moisturizer. SH stated that the dryness had not worsened despite
continued use of the product. The subject stated that she has experienced a similar
response in the past when using other facial cleansing products.

APPENDIX IV (cont.)
SUBJECT-PERCEIVED DISCOMFORT/IRRITATIONThe subject was Dermatologist-assessed as having pre-existing moderate generalerythema, closed comedones of the forehead, actinic keratoses, telangiectasia androsacea. (no change)
Judgment: No follow-up testing was conducted. The subject’s response of visible dryness was notcorroborated at any time by the consultant Dermatologist. Additionally, this response
was not considered to be specifically related to use of the test product as the subject selfacknowledged a personal history of similar response when using other facial cleansing
products. This response will not impact the overall safety in use of the 5-in-1 Facial
Cleanser.

13

Distributed for Comment Only -- Do Not Cite or Quote

APPENDIX IV (cont.)
SUBJECT-PERCEIVED DISCOMFORT/IRRITATIONNJ #12

Testing Center-Assessed Skin Sensitivity:
Self-Assessed Skin Sensitivity:
Self-Assessed Skin Type:
Facial Cleanser User:
Facial Scrub User:
Facial Moisturizer User:

B
Sensitive
Normal to Dry
Cetaphil
None
AveenoCASE CHRONOLOGY
3/8/16reported to the Testing Center for her scheduled initial visit. She was given
5-in-1 Facial Cleanser to use twice a day, morning and evening, for four weeks.
Subjects were instructed to use the product to cleanse the face each morning. For
nighttime use, the subjects were instructed to use the product as a facial cleanser threenights, as an exfoliating cleansing scrub two nights, and as a deep purifying cleansing
mask on the remaining two nights each week. Subjects were allowed to continue use of
their own regular moisturizer.
She was Dermatologist-assessed as having mild central facial erythema, suborbital
edema/erythema, open comedones of the nose and one closed comedone of the rightcheek.

3/28/16

returned to the Testing Center for her scheduled interim visit. She stated that, witheach use of the 5-in-1 product, she experienced a tingling sensation. The tingling wasmoderate in intensity and lasted only fifteen to twenty seconds each time. The
14

Distributed for Comment Only -- Do Not Cite or Quote

discomfort was not accompanied by any visible signs of irritation. The subject did not
feel the need to discontinue product use at any time.
She was Staff-assessed as having pre-existing mild central facial erythema, suborbital
edema/erythema, open comedones of the nose and a closed comedone of the right cheek.
(no change) [The subject was unable to return for the scheduled interim visit with the
Dermatologist.]
Instructions: The subject was asked to continue using the product as instructed. She will contact theTesting Center if her response worsens. She will return to the Testing Center for herscheduled final visit.

4/5/15returned to the Testing Center for her scheduled final visit. She stated that, during
the final two weeks of 5-in-1 product use, she continued to experience moderate tinglingon the face. NJ noted that the tingling seemed to increase in intensity the longer the
product was left on the face, as in mask use; she was unable to keep the product on the
APPENDIX IV (cont.)
SUBJECT-PERCEIVED DISCOMFORT/IRRITATION

face for the full recommended five minutes as a mask. NJ did not observe any visible
signs of irritation during the study period and did not fully discontinue product use at
any time.
The subject was Dermatologist-assessed as having one to two papules of the chin withpre-existing mild central facial erythema, suborbital edema/erythema, open comedonesof the nose and a closed comedone of the right cheek. (no change)
Judgment: No follow-up testing was conducted. The subject’s response of discomfort wastransient in nature, lasting less than thirty seconds for the majority of uses. Although
she was not comfortable with using the product as a mask for the full five minutes
recommended in the usage instructions, she was able to use the product as a mask forseveral minutes. Additionally, the subject’s response was not accompanied by any
visible signs of irritation at any time throughout the study period. Given the transient
duration of the subject’s response and absence of visible irritation, this response was notconsidered to impact the overall safety in use of the 5-in-1 Cleanser.

15

Distributed for Comment Only -- Do Not Cite or Quote

APPENDIX IV (cont.)
SUBJECT-PERCEIVED DISCOMFORT/IRRITATION

CL #50

Testing Center-Assessed Skin Sensitivity:
Self-Assessed Skin Sensitivity:
Self-Assessed Skin Type:
Facial Cleanser User:
Facial Scrub User:
Facial Moisturizer User:

C
NormalNormalNone
VariousEstee Lauder

CASE CHRONOLOGY
3/8/16reported to the Testing Center for her scheduled initial visit. She was given
5-in-1 Facial Cleanser to use twice a day, morning and evening, for four weeks.
Subjects were instructed to use the product to cleanse the face each morning. For
nighttime use, the subjects were instructed to use the product as a facial cleanser threenights, as an exfoliating cleansing scrub two nights, and as a deep purifying cleansing
mask on the remaining two nights each week. Subjects were allowed to continue use of
their own regular moisturizer.
She was Dermatologist-assessed as having central facial erythema, seborrheic dermatitisof the sides of the nose and rosacea.

3/22/16

returned to the Testing Center for her scheduled interim visit. She stated that she
did not experience any discomfort and/or irritation while using the 5-in-1 Cleanser.
She was Dermatologist-assessed as having papules of the right side of the chin andmacules of the nose with pre-existing central facial erythema, seborrheic dermatitis of
the sides of the nose and rosacea.
16

Distributed for Comment Only -- Do Not Cite or Quote

Instructions: The subject was asked to continue using the product as instructed. She will return to the
Testing Center for her scheduled final visit.
4/5/15returned to the Testing Center for her scheduled final visit. She stated that, during
the final two weeks of using the 5-in-1 Cleanser, she observed redness around the nose.
The redness occurred with each product use, was unaccompanied by any sensations of
discomfort, and resolved spontaneously within one hour.
The subject was Dermatologist-assessed as having pre-existing papules of the right sideof the chin, central facial erythema, seborrheic dermatitis of the sides of the nose androsacea. Macules were clear.

Judgment: No follow-up testing was conducted. The subject’s response of visible redness was
episodic in nature and was not corroborated at any time by the consultant Dermatologist.
Additionally, the response was limited to the nose area only despite use of the productover the entire face. This response will not impact the overall safety in use of the 5-in1 Facial Cleanser.
APPENDIX IV (cont.)
SUBJECT-PERCEIVED DISCOMFORT/IRRITATION

EN #28

Testing Center-Assessed Skin Sensitivity:
Self-Assessed Skin Sensitivity:
Self-Assessed Skin Type:
Facial Cleanser User:
Facial Scrub User:
Facial Moisturizer User:C
Sensitive
Normal to Dry
Ole Henriksen Pure Truth
None
Lush Imperialis

CASE CHRONOLOGY
3/8/16reported to the Testing Center for her scheduled initial visit. She was given
5-in-1 Facial Cleanser to use twice a day, morning and evening, for four weeks.
Subjects were instructed to use the product to cleanse the face each morning. For
nighttime use, the subjects were instructed to use the product as a facial cleanser threenights, as an exfoliating cleansing scrub two nights, and as a deep purifying cleansing
mask on the remaining two nights each week. Subjects were allowed to continue use of
their own regular moisturizer.
She was Dermatologist-assessed as having erythema of the central face/chin/ nasolabial
fold, scattered open comedones, scattered papules and rosacea.

3/22/16

returned to the Testing Center for her scheduled interim visit. She stated that, while
using the product as an exfoliating scrub, she experienced slight burning which persisted
until the subject applied her own facial moisturizer. The discomfort was not
17

Distributed for Comment Only -- Do Not Cite or Quoteaccompanied by any visible signs of irritation. EN noted that she had experienced asimilar response in the past when using other facial scrub products.
She was Dermatologist-assessed as having pre-existing erythema of the central
face/chin/nasolabial fold, scattered open comedones, scattered papules and rosacea. (nochange)Instructions: The subject was asked to continue using the product as instructed. She will contact theTesting Center if her response worsens. She will return to the Testing Center for herscheduled final visit.
4/5/15returned to the Testing Center for her scheduled final visit. She stated that, during
the final two weeks of product use as a facial scrub, she continued to experience slightburning which persisted until application of her own regular moisturizer. EN reiterated
her past history of similar response when using other facial scrub products.
The subject was pre-existing erythema of the central face/chin/nasolabial fold, scatteredopen comedones, scattered papules and rosacea. (no change)
APPENDIX IV (cont.)
SUBJECT-PERCEIVED DISCOMFORT/IRRITATION

Judgment: No follow-up testing was conducted. The subject’s response of burning while using the
product as an exfoliating scrub was not considered to be specifically related to use of thetest product as the subject self-acknowledged a personal history of similar responsewhen using other facial scrub products. This response will not impact the overall safety
in use of the 5-in-1 Facial Cleanser.

18

Distributed for Comment Only -- Do Not Cite or Quote

APPENDIX IV (cont.)
SUBJECT-PERCEIVED DISCOMFORT/IRRITATION

RO #2

Testing Center-Assessed Skin Sensitivity:
Self-Assessed Skin Sensitivity:
Self-Assessed Skin Type:
Facial Cleanser User:
Facial Scrub User:
Facial Moisturizer User:C
Sensitive
Normal to Dry
Olay Foaming
None
Olay/Cocoa Butter

CASE CHRONOLOGY
3/8/16reported to the Testing Center for her scheduled initial visit. She was given
5-in-1 Facial Cleanser to use twice a day, morning and evening, for four weeks.
Subjects were instructed to use the product to cleanse the face each morning. For
nighttime use, the subjects were instructed to use the product as a facial cleanser threenights, as an exfoliating cleansing scrub two nights, and as a deep purifying cleansing
mask on the remaining two nights each week. Subjects were allowed to continue use of
their own regular moisturizer.
She was Dermatologist-assessed as having mild central facial erythema, closed
comedones of the cheeks and scatter papules.

3/24/16

returned to the Testing Center for her scheduled interim visit. She stated that,
following use of the product as a purifying mask and as an exfoliating scrub, she noted
redness of the cheeks and forehead. The redness persisted for fifteen to twenty minutes
19Distributed for Comment Only -- Do Not Cite or Quote

and was accompanied by a sensation of dryness; the sensation of dryness was relievedby moisturizer application.
She was Staff-assessed as having pre-existing mild central facial erythema, closed
comedones of the cheeks and scattered papules. (no change) [The subject was unable toreturn for the Dermatologist supervised interim visit.]
Instructions: The subject was asked to continue using the product as instructed. She will contact theTesting Center if her response worsens. She will return to the Testing Center for herscheduled final visit.

4/5/15returned to the Testing Center for her scheduled final visit. She stated that, during
the final two weeks of using the product as a purifying mask and exfoliating scrub, sheobserved redness of the cheeks and forehead which persisted for approximately fifteen
to twenty minutes each time. The subject also continued to experience a sensation ofdryness which was relieved by use of her own regular moisturizer. RO did notdiscontinue use of the 5-in-1 Cleanser at any time during the study period.
APPENDIX IV (cont.)
SUBJECT-PERCEIVED DISCOMFORT/IRRITATIONThe subject was Dermatologist-assessed as having pre-existing mild central facial
erythema, closed comedones of the cheeks and scattered papules. (no change)
Judgment: No follow-up testing was conducted. The subject’s response of redness did not worsen
despite continued use of the product. The accompanying sensation of dryness was
relieved by use of the subject’s own moisturizer. As the subject was able to continueuse of the product throughout the four-week study period and the Dermatologist did notobserve any visible irritation at any time, this response will not impact the overall safety
in use of the 5-in-1 Facial Cleanser.

20

Distributed for Comment Only -- Do Not Cite or Quote

APPENDIX IV (cont.)
SUBJECT-PERCEIVED DISCOMFORT/IRRITATION

MR #13

Testing Center-Assessed Skin Sensitivity: A
Self-Assessed Skin Sensitivity:
Very Sensitive
Self-Assessed Skin Type:
Normal to Dry
Facial Cleanser User:
Gentle Cleanser
Facial Scrub User:
None
Facial Moisturizer User:
Perfectly Posh
CASE CHRONOLOGY

3/8/16reported to the Testing Center for her scheduled initial visit. She was given
5-in-1 Facial Cleanser to use twice a day, morning and evening, for four weeks.
Subjects were instructed to use the product to cleanse the face each morning. For
nighttime use, the subjects were instructed to use the product as a facial cleanser threenights, as an exfoliating cleansing scrub two nights, and as a deep purifying cleansing
mask on the remaining two nights each week. Subjects were allowed to continue use of
their own regular moisturizer.
She was Dermatologist-assessed as having moderate generalized erythema, moderatescaling of the lower face and glabella, open comedones of the chin, scattered closed
comedones and rosacea.

3/22/16

returned to the Testing Center for her scheduled interim visit. She stated that,while using the product as a purifying mask, she experienced a burning sensation. The
21

Distributed for Comment Only -- Do Not Cite or Quoteburning was moderate in intensity and lasted while the product was on the face and forapproximately one minute following removal. The discomfort was not accompanied byany visible signs of irritation.
She was Dermatologist-assessed as having pre-existing seborrheic dermatitis of thesides of the nose with pre-existing moderate generalized erythema and moderate scalingof the lower face and glabella. Comedones were clear.
Instructions: The subject was asked to continue using the product as instructed. She will contact theTesting Center if her response worsens. She will return to the Testing Center for herscheduled final visit.
4/5/15returned to the Testing Center for her scheduled final visit. She stated that, during
the final two weeks of product use, she did not experience any episodes of discomfort
when using the product in any form.

APPENDIX IV (cont.)
SUBJECT-PERCEIVED DISCOMFORT/IRRITATIONThe subject was Dermatologist-assessed as having open comedones of the chin with
scattered closed comedones with pre-existing moderate generalized erythema androsacea. Scaling and seborrheic dermatitis were clear.
Judgment: No follow-up testing was conducted. The subject’s response of discomfort resolved
spontaneously without recurrence despite continued product use. This response will
not impact the overall safety in use of the 5-in-1 Facial Cleanser.

22

Distributed for Comment Only -- Do Not Cite or Quote

contains 1.75% Bentonite

Distributed for Comment Only -- Do Not Cite or Quote

FINAL REPORTSTUDY TITLE:
A 14-Day Cumulative Irritation Assay
PROTOCOL:GUIDELINES FOR THE CONDUCT OF THE STUDY:
All procedures were conducted in compliance with the regulations of the Food and Drug
Administration (FDA) ([21CFR 50, 56, 312] ICH-GCP Consolidated Guidelines, May 9,1997 Federal Register) and in accordance withStandard Operating Procedures(SOP’s).

SPONSOR:SPONSOR STUDY:
Avon Submission Form (ASF) dated June 6, 2012
SPONSOR REPRESENTATIVE:OBJECTIVE:
This test is designed to furnish data on the primary irritancy potential o f topically applied
substances in human skin.

Page 1Distributed for Comment Only -- Do Not Cite or Quote

Lotion B w/SPF coded

DESIGN RATIONALE:
A repeat insult patch test study wherein the test materials were applied under occlusive
dressings to designated test sites on the back or upper arm continuously and repeatedly
to the same site for a period of 14 days (2,3).
PRINCIPAL INVESTIGATOR:(Board Certified Dermatologist)
Medical Director,
Telephone:
FAX:

ADMINISTATIVE STRUCTURE:(Panel Recruitment/Initial Screening)(Patcher), M.D. and(Expert Graders)(Quality Assurance)

TESTING FACILITY:DATES OF STUDY CONDUCT:The study was conducted from June 11, 2012 through June 25, 2012.

PANEL COMPOSITION:
Healthy, normal, adult Caucasian volunteers over the age of 18 years of both sexes withno blemishes, excess hair or other marks on their back or upper arms that would
obscure grading of the test sites served as subjects.

Page 2

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Lotion B w/SPF coded

Inclusion Criteria:
1. Healthy adult male and female volunteers between the ages of 18 and 65 years.
2. Subjects willing to follow the study requirements and provide a signed informed
consent.
Exclusion Criteria:
1. History of recurrent dermatological diseases, e.g., psoriasis, atopic eczema,
chronic urticaria, vitiligo, etc.
2. History of allergy or hypersensitivity to cosmetics, toiletries, or otherdermatological products.
3. History of allergy or hypersensitivity to sunscreens.
4. History of allergy or hypersensitivity to any type of tape.
5. Scars, moles or other blemishes over the upper arm or back, which could
interfere with the study.
6. Subjects receiving systemic or topical drugs including steroidal or non -steroidal
anti-inflammatory drugs, or medications which could interfere with thedevelopment of an inflammatory response, e.g., immunosuppressive age nts orretinoids
7. Subjects with any significant internal diseases, e.g., cardiac, pulmonary, renal,
hepatic, etc.
8. Pregnancy or mothers who were breastfeeding or planning a pregnancy
9. Other conditions considered by the Investigator as sound reasons fordisqualification from enrollment into the study.

INFORMED CONSENT:
After the protocol, reasons for the study, possible associated risks and potential benefits
or risks of the treatment had been completely explained, signed, informed subject
consent was obtained from each volunteer prior to the start of the study. Copies of allconsent forms are on file at.

TEST MATERIAL:
One test sample labeled Lotion B w/SPF and coded

was supplied by thesponsor and tested as supplied viz. neat (as is). One (1) jar was supplied for testing

Page 3

Distributed for Comment Only -- Do Not Cite or Quote

Lotion B w/SPF coded

purposes. In addition, one other test product labeled “Lotion C w/SPF" and coded
was included in this panel for comparison.

HANDLING OF STUDY DOCUMENTS:
All study related documents, case report forms (CRF's), consent forms and any data
generated was kept under secure lock in the technician's office during the study.

CASE REPORT FORMS:
All case report forms (CRFs) were completed in actual time during each patient’s visit.

RECORDING OF DATA AND CORRECTIONS:All data and information was recorded on specific case report forms (CRF’s) and thisinformation was recorded/or legibly printed in black ink. Any errors were crossed out
with a single line and the correct entry made in ink and initialed and date d by theInvestigator or by the Study Coordinator.
SUBJECT ASSIGNMENT:
Volunteer subjects were screened and qualifying subjects were selected as describedabove and assigned a subject number. The initials of each subject accepted into thestudy were recorded sequentially as they were enrolled.

METHOD AND PROCEDURES:
Approximately 0.05ml of the test material was spread uniformly onto a 15mm diametercircular disc of non-absorbing cotton cloth (Webril). The treated circular disc of Webril
cotton cloth was then applied to a designated skin site measuring 15mm in diameter on
the upper arm or back. The site was then covered with occlusive tape (Blenderm, 3M)
and the entire patch fastened to the skin with Scanpor Tape to ensure intimate contact
with the skin. This procedure was repeated daily Mondays through Fridays after
evaluation of the test site with a daily fresh application of the test material for a total of
14 days. The patch remained in place over the weekends (Saturdays and Sundays). In
addition to the test product and the comparator product (Lotion C w/SPF coded), one site was also treated with 0.05ml of 0.25% SLS (sodium lauryl sulfate) as aPage 4

Distributed for Comment Only -- Do Not Cite or Quote

Lotion B w/SPF coded

positive control while another site was treated with plain cotton webril and served as anegative control.
ASSESSMENT AND GRADING OF RESPONSES:
Irritant reactions which may have been provoked during the study were recorded daily.
All test sites were graded daily after removal of the patches for possible irritation using
the following scale:
0 = normal looking skin
1 = very faint erythema with indistinct borders
2 = minimal or mild erythema with at least one discernable border
3 = moderate erythema with sharply distinct borders
4 = deep, intense erythema
5 = deep, intense erythema with edema (a palpable, raised or elevated lesion)
Other Notations:

V = Vesicles
E = Erosions
F = Fissuring

Test sites achieving a grade 3 or greater score were discontinued and that grade (3 or 4)
was carried through for the remainder of the test days for the purpose of calculating the
cumulative irritation index of the test product.
RESULTS:A total of 26 healthy Caucasian panelists who qualified were enrolled into this study.
There was a total of 20 females and 06 males ranging in age from 21 to 63 years. One
subject #13 (initials R-K, a female) failed to maintain the scheduled study visits and was
dropped from the study for lack of compliance. The remaining 25 panelists completed
this investigation as outlined instandard 14-Day Cumulative Irritation Assay

protocol. The demography is shown in Table 1. There were no protocol deviations. No
adverse effects of any kind were observed in any of the test panelists.
Irritation:
The individual daily and cumulative irritation scores for each test site are shown in thetables in Appendix A. The comparator product labeled Lotion C w/SPF and coded
Page 5

Distributed for Comment Only -- Do Not Cite or Quote

Lotion B w/SPF coded

produced a total cumulative irritation score of “18” and a cumulative irritationindex (CII) of 0.02. The test product labeled Lotion B w/SPF and coded
produced a total cumulative score of “4” and a CII of “0.01”. By contrast, the 0.25% SLS
resulted in a CII of 0.55 (severe irritation potential). The mean irritation scores andCumulative Irritation Indices are summarized in Table 2.
CONCLUSIONS:
The test product coded(Lotion B w/SPF) was found to possess a“negligible” irritation potential in human skin while the comparator product coded(Lotion C w/SPF) was also found to possess a “negligible" irritation potential in
human skin.

Page 6

Distributed for Comment Only -- Do Not Cite or Quote

Lotion B w/SPF coded

REFERENCE:(1)

Jackson, E.M.:
A Modified Cumulative Patch Test to Substantiate Hypoallergenic Claims.
Cosmetic Dermatology. Vol. 7, pages 44-46, 1994.

(2) Philips, L., Steinberg, M., Maibach, H.I. and Akers, W.A.:
A Comparison of Rabbit and Human Skin Response to Certain Irritants.
Toxicol.Appl.Pharmacol. 21: 369-382, 1972.
(3) Lanman, B.M., Elvers, W.B. and Howard, C.S.: The Role of Human
Patch Testing in a Product Development Program. In: Proceedings,
Joint Conference on Cosmetic Sciences. The Toilet Goods Association,Inc., Washington, DC, pp. 135-145, 1968.

Page 7

Distributed for Comment Only -- Do Not Cite or Quote

Lotion B w/SPF coded

TABLE 1

DEMOGRAPHIC DATA

Subject
Number:
01
02
03
04
05
06
07
08
09
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26

Subject
Initials:

Age:

Sex:

Race:

28
21
63
63
39
49
37
29
44
40
62
46
32
58
56
59
29
21
54
53
47
56
54
58
55
30

F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
M
F
F
F
M
M
M
M
F
M

C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C

C = CaucasianPage 8

Distributed for Comment Only -- Do Not Cite or Quote

Lotion B w/SPF coded

TABLE 2
Mean and Cumulative Irritation Indices of Two Coded Test Products(N = 25)
Lotion B
coded

Lotion C
coded

Plain
CottonWebril

0.25% SLS

Sum of Cumulative
Scores

4

18

0

416

Mean Cumulative
Irritation Score

0.16

0.72

0

16.64

Mean Daily
Irritation Score

0.02

0.07

0

1.66

Cumulative
Irritation Index

0.01

0.02

0

0.55

Negligible

Negligible

Negligible

SevereIrritation Potential

Page 9

Distributed for Comment Only -- Do Not Cite or Quote

APPENDIX A
Cumulative Irritation Scores for Each Test Sitefor Comment Only -- Do Not Cite or Quote
DAILY Distributed
AND CUMULATIVEIRRITATION SCORES

Sample: Lotion B coded- tested as supplied

DAYS

1

2

3

4

5

6

7

8

9

10

11

12

13

14

Cumulative

Subject Number

T

W

Th

F

S

S

M

T

W

Th

F

S

S

M

Score

1
2
3
4
5
6
7
8
9
10
11
12
13*
14
15
16
17
18
19
20
21
22
23
24
25
26

0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
1
0
0
0
0
0

0
0
0
0
0
0
1
0
0
0
0
0

0
0
0
0
0
0
1
0
0
0
0
0

0
0
0
0
0
0
1
0
0
0
0
0

0
0
0
0
0
0
4
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0
0
1

0
0
0
0
0
0
0
0
0
0
0
0
0
1

0
0
0
0
0
0
0
0
0
0
0
0
0
1

0
0
0
0
0
0
0
0
0
0
0
0
0
1

0
0
0
0
0
0
0
0
0
0
0
0
0
4

Σ

Mean Cumulative Irritation Score:
Mean Daily Irritation Scores:
Cumulative Irritation Index (CII):* Dropped from the study

0.16
0.02
0.01

Distributed for Comment Only -- Do Not Cite or Quote

DAILY AND CUMULATIVE IRRITATION SCORES
Sample: Lotion C w/SPF coded(standard) - tested as supplied

DAYS

1

2

3

4

5

6

7

8

9

10

11

12

13

14

Cumulative

Subject Number

T

W

Th

F

S

S

M

T

W

Th

F

S

S

M

Score

1
2
3
4
5
6
7
8
9
10
11
12
13*
14
15
16
17
18
19
20
21
22
23
24
25
26

0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
1
0
0
0
0
0

0
0
0
0
0
0
1
0
0
0
0
0

0
0
0
0
0
0
1
0
0
0
0
0

0
0
0
0
0
0
1
0
0
0
0
0

0
0
0
0
0
0
1
0
0
0
0
0

1
0
0
0
0
0
1
0
0
0
0
0

1
0
0
0
0
0
1
0
0
0
0
0

1
0
0
0
0
0
1
0
0
0
0
0

3
0
0
0
0
0
8
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0
0
1

0
0
0
0
0
0
0
0
0
0
0
0
0
1

0
0
0
0
0
0
0
0
0
0
0
0
0
1

0
0
0
0
0
0
0
0
0
0
0
0
0
1

0
0
0
0
0
0
0
0
0
0
0
0
0
1

0
0
0
0
1
0
0
0
0
0
0
1
0
4

0
0
0
0
1
0
0
0
0
0
0
1
0
4

0
0
0
0
1
0
0
0
0
0
0
2
0
5

0
0
0
0
3
0
0
0
0
0
0
4
0
18

Σ

Mean Cumulative Irritation Score:
Mean Daily Irritation Scores:

0.72

Cumulative Irritation Index (CII):*Dropped from the study

0.02

0.07

Distributed for Comment Only -- Do Not Cite or Quote

DAILY AND CUMULATIVE IRRITATION SCORES
Sample: Plain Cotton Webril
DAYS

1

2

3

4

5

6

7

8

9

10

11

12

13

14

Cumulative

Subject Number

T

W

Th

F

S

S

M

T

W

Th

F

S

S

M

Score

1
2
3
4
5
6
7
8
9
10
11
12
13*
14
15
16
17
18
19
20
21
22
23
24
25
26

0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0
0
0

Σ

Mean Cumulative Irritation Score:
Mean Daily Irritation Scores:
Cumulative Irritation Index (CII):*Dropped from the study

0.00
0.00
0.00

Distributed for Comment Only -- Do Not Cite or Quote

DAILY AND CUMULATIVE IRRITATION SCORES
Sample: 0.25% Sodium Lauryl Sulfate (SLS)
DAYS

1

2

3

4

5

6

7

8

9

10

11

12

13

14

Cumulative

Subject Number

T

W

Th

F

S

S

M

T

W

Th

F

S

S

M

Score

1
2
3
4
5
6
7
8
9
10
11
12
13*
14
15
16
17
18
19
20
21
22
23
24
25
26

0
0
0
0
0
0
0
0
0
0
0
0

0
1
0
0
0
0
0
0
0
0
0
0

1
1
1
1
1
0
0
0
0
0
0
1

2
2
2
2
1
0
1
1
0
1
0
3

2
2
2
2
1
1
1
1
0
1
1
-

3
3
2
3
1
1
1
1
1
2
1
-

3
2
2
2
2
1
2
1
-

3
2
2
3
1
3
2
-

3
3
1
2
-

2
2
-

20
21
19
20
15
12
13
14
6
15
9
22

0
0
0
0
0
0
0
1
0
0
0
0
0
1

0
0
0
0
0
0
0
1
0
0
0
0
0
2

1
0
1
1
0
1
0
1
1
0
1
1
1
15

3
1
2
3
0
1
1
3
2
0
1
2
1
35

1
3
1
2
1
3
1
1
2
2
43

1
1
2
2
2
2
2
2
51

1
1
3
2
2
3
3
3
60

2
2
3
3
68

2
2
70

2
2
71

22
10
21
22
9
18
15
24
21
14
17
19
18
416

Σ

Mean Cumulative Irritation Score:
Mean Daily Irritation Scores:
Cumulative Irritation Index (CII):*Dropped from the study

16.64
1.66
0.55

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

contains 8% Bentonite

Distributed for Comment Only -- Do Not Cite or Quote

Memorandum

TO:

Bart Heldreth, Ph.D.
Executive Director - Cosmetic Ingredient Review

FROM:

Carol Eisenmann, Ph.D.
Personal Care Products Council

DATE:

April 25, 2022

SUBJECT:

Bentonite and Kaolin

The Innovation Company. 2022. Physical properties Bentonite and Kaolin.

Distributed for Comment Only -- Do Not Cite or Quote

The Innovation Company

April 2022

Physical Properties Bentonite and Kaolin
Property
Particle Size Distribution (PSD) (µm) at D50
Specific Surface Area (SSA) (m2/g)
Surface Tension
Capillary Constant (mm2)
Photo-stability

Bentonite
61.1
12.6
Above 90
22.2
Delta E over 2 at 2.94
photoreactive based on EU
ISO 24443:2-39.6 (negative charge)
Increase 4% in 5 minutes

Zeta Potential at epidermal pH of 5.3 (mV)
In Situ Double Laser Confocal (DLC)
Microscopy** Allows observation of the skin matrix down to 200 µm plus

Kaolin
3.1
14.74
Above 90
23.1
Delta E over 2 at 0.71
photostable based on EU ISO
24443:2-51.2 (negative charge)
Increase 6% in 5 minutes

Distributed for Comment Only -- Do Not Cite or Quote

Memorandum

TO:

Bart Heldreth, Ph.D.
Executive Director - Cosmetic Ingredient Review

FROM:

Carol Eisenmann, Ph.D.
Personal Care Products Council

DATE:

April 26, 2022

SUBJECT:

Bentonite and Kaolin

Anonymous. 2004. Clinical safety evaluation: Repeated insult patch test (face cream contains 7.5%
Bentonite).
Anonymous. 1997. Clinical safety evaluation: Repeated insult patch test (clay mask contains 40%
Kaolin).

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

face creams contains 7.5% Bentonite

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

clay mask contains 40% Kaolin

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Memorandum

TO:

Bart Heldreth, Ph.D.
Executive Director - Cosmetic Ingredient Review

FROM:

Carol Eisenmann, Ph.D.
Personal Care Products Council

DATE:

April 29, 2022

SUBJECT:

Montmorillonite

Anonymous. 2022. Dermal irritation and sensitization data - Montmorillonite (ingredient tested
contains 38% Montmorillonite).

Distributed for Comment Only -- Do Not Cite or Quote

April 2022
Dermal Irritation and Sensitization Data - Montmorillonite
Test article is a cosmetic Ingredient mixture containing 38% Montmorillonite plus other ingredients
including an EU colorant*Skin Irritation Test (SIT) using the EpidermTM Skin Model, according to the OECD TG 439*Summary:-The test article was administered to the test system without dilution (neat).
Since the test article was a powder, 25 μL of Calcium & Magnesium Free Dulbecco’s Phosphate
Buffered Saline (CMF-DPBS) were applied to the tissues prior to addition of approximately 25
mg of the test article. The test article was administered using a dosing spoon.
-Direct MTT Reduction Test
The test article was observed to directly reduce MTT. For this test article, a killed control
experiment was run concurrently with viable tissues. Additional calculations were performed toaccount for the direct MTT reduction-Assessment of Colored or Staining Materials
The test article was considered to have probable photometric MTT interference. A colorant
control experiment was performed concurrently for the test article in the definitive assay.
Additional calculations were performed to account for the photometric interference.
-Test Article & Control Exposures
The test article, the positive control (5% Sodium Dodecyl Sulfate (SDS), and the negative
control (CMF-DPBS) were treated in triplicate EpiDermTM tissues for a 60 ± 1 minute exposure
period, followed by a 42 ± 2-hour post-exposure incubation period.
After application of the test article, sterile glass rods were used to spread the test article overthe surface of the tissues.
Since the test article was observed to directly reduce or interfere with MTT and was also noted
to have potential for photometric interference, an additional set of controls was tested
concurrently with the colorant control and killed control experiments. The colorant control-killedcontrol tissues were killed control tissues that incubated in Maintenance Medium instead ofMTT. Additional calculations were performed to calculate the final optical density values for thistest article.
-Result
Mean Viability = 105.7%-Conclusion= Not irritant for the skin1Distributed for Comment Only -- Do Not Cite or Quote* In vitro sensitization-Introduction
The KeratinoSensTM assay is a cell-based assay with a reporter cell line to detect potential skinsensitizers by their ability to induce the Nrf2-response.
This assay has been validated for a broad range of low-molecular weight chemicals and it was
found to respond to skin sensitizers from a broad range of so called applicability domains, i.e.
chemicals reacting with proteins by different mechanisms. It was validated by ECVAM andproposed to be used as part of an integrated approach for testing and assessment (IATA).
-Experimental
The test substance was dissolved in cell culture medium and tested according to the standard
operating procedure of the KeratinoSensTM assay at 12 concentrations in three repetitions, eachtime in three replicates. After a 48 h incubation time, luciferase induction and cellular viability ateach of the concentrations were determined.
-Results
The test article was weakly toxic to the KeratinoSens™ cells. The test article did induce theluciferase gene above the threshold of 1.5 in one of three repetitions and it is thus rated
negative in the KeratinoSens™ assay, as a result of 1 positive from 3 repetitions is considerednegative. Also the induction observed in the positive repetition was only at the maximal
concentration according to the prediction model (200 µg/ml) and close to the threshold of 1.5(1.57-fold) further supporting the negative rating.
-Conclusion: non sensitizer

2

Distributed for Comment Only -- Do Not Cite or Quote

Memorandum

TO:

Bart Heldreth, Ph.D.
Executive Director - Cosmetic Ingredient Review

FROM:

Carol Eisenmann, Ph.D.
Personal Care Products Council

DATE:

May 11, 2022

SUBJECT:

Hectorite

Anonymous. 2022. Summary information - Hectorite.

Distributed for Comment Only -- Do Not Cite or Quote

May 2022
Summary Information – Hectorite
Particle Size Information:
The following mean and range data was determined for several hectorite products.
SampleHectorite Product 1
Hectorite Product 2
Hectorite Product 3
Hectorite Product 4
Hectorite Product 5

Mean Particle Size (μm)
20.8
21.8
24.4
25.4
19.9

Particle Range (μm)
2-9 – 115.1
3.3 – 114.8
3.3 – 131.7
3.3 – 131.6
3.3 – 114.9

Chronic Inhalation Data:
Chronic inhalation data for hectorite are not available.
Human Dermal Irritation and Sensitization Data at the Maximum Concentration of Use:
Human data are not available. The following animal toxicological study results are available.
• Dermal Irritation – Draize test / 16 CFR 1500.41 / Rabbits / 100% hectorite sample / Result – Nonirritating (score - 0.0) / performed 1980
• Dermal Sensitization – Buehler test / Guinea Pigs / 50% hectorite sample / Result – Non-sensitizing (noevidence of hypersensitivity) / performed 1973

Distributed for Comment Only -- Do Not Cite or Quote

Concentration of Use by FDA Product Category – Clays*
Attapulgite
Bentonite
Clay
Ingredient

Fuller's Earth
Hectorite
IlliteProduct Category

Bentonite
Bentonite
Bentonite
Bentonite
Bentonite
Bentonite
Bentonite
Bentonite
Bentonite

Eyeliners
Eye shadows
Mascaras
Hair bleaches
Blushers
Other makeup preparations
Other manicuring preparations
Bath soaps and detergents
Skin cleansing (cold creams, cleansing lotions, liquids, andpads)
Face and neck products
Not spray
Body and hand products
Not spray
Paste masks and mud packs
Suntan products
Not spray
Spray
Skin cleansing (cold creams, cleansing lotions, liquids, andpads)
Eyeliners
Hair conditioners
Shampoos (noncoloring)
Tonics, dressings, and other hair grooming aids
Not spray
Hair shampoos (coloring)Foundations
Face and neck products
Not spray
Other baby products
Tonics, dressings, and other hair grooming aids
Bath soaps and detergents
Skin cleansing (cold creams, cleansing lotions, liquids, andpads)
Paste masks and mud packs
Other baby products
Eyebrow pencils
Eyeliners
Eye shadows

Bentonite
Bentonite
Bentonite
Bentonite
Clay
Hectorite
Hectorite
Hectorite
Hectorite
Hectorite
Hectorite
Hectorite
IlliteIlliteIlliteIlliteIlliteKaolinKaolinKaolinKaolinKaolinMontmorillonite

1

Maximum
Concentration of Use
0.00025%
4.5%
1.5%
17.3%
4%
0.6%
2.8%
0.22-4.7%
1.3-7%
8%
8%
1.5-10%
2.5%
0.9%
4.5%
0.057%
0.13%
0.1%
0.13%
0.1%
1.5%
0.1%
0.0015%0.025%
0.34%
3.8%
1-2%
0.0085%
4.3%
0.82-2%0.35-8.5%

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KaolinKaolinKaolinKaolinKaolinKaolinKaolinKaolinKaolinKaolinKaolinKaolinKaolinKaolinKaolinKaolinKaolinKaolinKaolinEye makeup removers
0.001%
Mascaras
0.5-4.7%
Hair conditioners
0.0005-26%
Shampoos (noncoloring)
0.058-0.14%
Tonics, dressings, and other hair grooming aids
0.0015-25%
Other hair preparations (noncoloring)
0.1%
Hair tints
5%
Hair lighteners with color
19.3%
Hair bleaches
19.5%
Blushers
0.05-15%
Face powders
0.01-15%
Foundations
0.5-6%
Lipstick0.0053-14.5%
Makeup bases
1%
Other makeup preparations
2-4%
Nail polish and enamel
0.023%
Other manicuring preparations
35.5-53.2%
Bath soaps and detergents
1-5%
Deodorants
Not spray
2.6%
KaolinShaving cream
0.25%
KaolinSkin cleansing (cold creams, cleansing lotions, liquids, and3.4-20%pads)
KaolinDepilatories
4%
KaolinFace and neck products
Not spray
0.11-16%
KaolinBody and hand products
Not spray
3.3-12%KaolinMoisturizing products
Not spray
0.2-1%
KaolinPaste masks and mud packs
5-33%
KaolinSkin fresheners
0.25%
KaolinOther skin care preparations
10-20.4%
Montmorillonite Skin cleansing (cold creams, cleansing lotions, liquids, and
0.3%
pads)
Montmorillonite Face and neck products
Not spray
1.2-2%
Montmorillonite Paste masks and mud packs
0.1-3%*Ingredients included in the title of the table but not found in the table were included in theconcentration of use survey, but no uses were reported.
Information collected in 2022
Table prepared: July 5, 2022

2

Distributed for Comment Only -- Do Not Cite or Quote

Memorandum
TO:

Bart Heldreth, Ph.D.
Executive Director - Cosmetic Ingredient Review

FROM:

Carol Eisenmann, Ph.D.
Personal Care Products Council

DATE:

August 17, 2022

SUBJECT:

KaolinInstitute for In Vitro Sciences, Inc. 2004. Tissue equivalent assay with Epiocular™ cultures(clay mask with 14.5% Kaolin).
TKL Research. 2004. Repeated insult patch study (clay mask with 14.5% Kaolin).

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Distributed for Comment Only -- Do Not Cite or QuoteTKL Study No.

TABLE OF CONTENTS
SIGNATURES ...................................................................................................................... 1
STATEMENT OF QUALITY ASSURANCE .......................................................................... 1
TITLE OF STUDY ................................................................................................................ 2
SPONSOR ........................................................................................................................... 2
STUDY MATERIAL .............................................................................................................. 2
DATE STUDY INITIATED .................................................................................................... 2
DATE STUDY COMPLETED ............................................................................................... 2
DATE OF REPORT .............................................................................................................. 2
INVESTIGATIVE PERSONNEL ........................................................................................... 3
CLINICAL SITE .................................................................................................................... 3
SUMMARY ........................................................................................................................... 4
1.0 OBJECTIVE................................................................................................................ 5
2.0 RATIONALE ............................................................................................................... 5
3.0 STUDY DESIGN ......................................................................................................... 5
3.1 STUDY POPULATION .................................................................................................. 5
3.1.1
3.1.2
3.1.3

Inclusion Criteria .................................................................................................... 5
Exclusion Criteria ................................................................................................... 6
Informed Consent................................................................................................... 6

3.2 DESCRIPTION OF STUDY ............................................................................................. 6
3.2.1
3.2.2
3.2.3

Outline of Study Procedures................................................................................... 6
Definitions Used for Grading Responses................................................................ 7
Evaluation of Responses........................................................................................ 8

4.0

NATURE OF STUDY MATERIAL ............................................................................... 8
4.1 STUDY MATERIAL SPECIFICATIONS ............................................................................. 8
4.2 STORAGE, HANDLING, AND DOCUMENTATION OF STUDY MATERIAL ............................... 8
4.3 APPLICATION OF STUDY MATERIAL .............................................................................. 8
4.4 DESCRIPTION OF PATCH CONDITIONS .......................................................................... 8
5.0 INTERPRETATION .................................................................................................... 9
6.0 PROTOCOL................................................................................................................ 9
7.0 DOCUMENTATION AND RETENTION OF DATA ..................................................... 9
8.0 RESULTS AND DISCUSSION ................................................................................. 10
9.0 CONCLUSION .......................................................................................................... 1010.0 REFERENCES ......................................................................................................... 11
APPENDICES
I
II
III
IV
V

SUMMARY TABLESDATA LISTINGS
CLINICAL MATERIAL RECORDINFORMED CONSENT DOCUMENT
PROTOCOL

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INVESTIGATIVE PERSONNEL
Jonathan S. Dosik, MD
Principal Investigator
Hilary Baldwin, MD
Consulting Dermatologist
Kathleen Georgeian
Clinical Research Coordinatorand Manager, Dermatologic Safety Testing
Tina Kelly
Assistant Manager, Dermatologic Safety Testing
Silvia Guadalupe
Assistant Clinical Research Coordinator
Holanda Ayon
Supervisor, Dermatologic Safety
Joanne Mruczek, RN
Senior Clinical Assistant

CLINICAL SITETKL RESEARCH, INC.
578 Driggs Ave
Brooklyn, NY 11211

TKL Study No.

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-5-

1.0

TKL Study No.

OBJECTIVE

The objective of this study was to determine the ability of the study material to cause sensitization byrepeated applications to the skin of humans under controlled patch study conditions.
2.0

RATIONALE

Substances that come into contact with human skin need to be evaluated for their propensity toirritate and/or sensitize. Once an appropriate pre-clinical safety evaluation has been performed, areproducible, standardized, quantitative patch evaluation procedure must be used to demonstrate thata particular material can be applied safely to human skin without significant risk of adverse
reactions. The method herein employed is generally accepted for such a purpose.
Repeated insult patch evaluation is a modified predictive patch study that can detect weak sensitizers
that require multiple applications to induce a cell-mediated (Type IV) immune response sufficient tocause an allergic reaction. Irritant reactions may also be detected using this evaluation method,
although this is not the primary purpose of this procedure. Results are interpreted according tointerpretive criteria based upon published works, as well as the clinical experience of TKL Research,
Inc. These interpretive criteria are periodically reviewed and amended as new information becomes
available.
3.0

STUDY DESIGN

3.1

STUDY POPULATIONA sufficient number of subjects were enrolled to provide 100 completed subjects.
3.1.1

Inclusion Criteria

Individuals eligible for inclusion in the study were those who:
1. were males or females, 18 years of age or older, in general good health;
2. were free of any systemic or dermatologic disorder which, in the opinion of the investigative
personnel, would have interfered with the study results or increased the risk of adverse events;
3. were of any skin type or race, providing the skin pigmentation would allow discernment oferythema;
4. had completed a medical screening procedure; and5. had read, understood, and signed an informed consent agreement.

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-6-

3.1.2

TKL Study No.

Exclusion Criteria

Individuals excluded from participation in the study were those who:
1. had any visible skin disease at the study site which, in the opinion of the investigative personnel,
would have interfered with the evaluation;
2. were receiving systemic or topical drugs or medication which, in the opinion of the investigative
personnel, would have interfered with the study results;
3. had psoriasis and/or active atopic dermatitis/eczema;
4. were females who were pregnant, planning to become pregnant during the study, or breastfeeding; and/or
5. had a known sensitivity to cosmetics, skin care products, or topical drugs as related to thematerial being evaluated.
3.1.3

Informed Consent

A properly executed informed consent document in compliance with FDA regulations (21 CFR Part50) was obtained from each subject prior to entering the study. The signed informed consent
document is maintained in the study file. In addition, the subject was provided with a copy of theinformed consent document (see Appendix IV).
3.2

DESCRIPTION OF STUDY

3.2.1

Outline of Study Procedures

Subjects participated in the study over a 6-week period involving 3 phases: (1) Induction, (2) Rest,and (3) Challenge. Prior to study entry, the subjects were screened to assure that they met theinclusion/exclusion criteria. Informed consent was obtained. Each subject was provided with aschedule of the study activities. All subjects were told to avoid wetting the patches and were asked
not to engage in activities that caused excessive perspiration. They were instructed to notify the staff
if they experienced any discomfort beyond mild itching or observed any adverse changes at the patchsites, while on the study or within 2 weeks of completing the study.
The Induction Phase consisted of 9 consecutive applications of the study material and subsequentevaluations of the patch sites. Prior to application of the patches, the sites were outlined with a skinmarker, eg, gentian violet. The subjects were required to remove the patches approximately 24 hours
after application. They returned to the facility at 48-hour intervals to have the sites evaluated andidentical patches applied to the same sites. Patches applied on Friday were removed by subjects after
24 hours. The sites were evaluated on the following Monday, ie, 72 hours after patch application*.
*

A Monday or Friday holiday could result in evaluation at 96 hours after patch application.

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TKL Study No

Following the ninth evaluation, the subjects were dismissed for a rest period of approximately 10-15
days.
Subjects who were absent once during the induction phase received a make-up (MU) patch at the lastinduction visit. The MU applications were graded 48 hours later at the MU visit, or were recorded as
N9G (no ninth grading).
The Challenge Phase was initiated during the sixth week of the study. Identical patches were applied
to sites previously unexposed to the study material. The patches were removed by subjects after 24hours and the sites graded after additional 24-hour and 48-hour periods (ie, 48 and 72 hours after
application). Rechallenge was performed whenever there was evidence of possible sensitization.
To be considered a completed case, a subject must have had 9 applications and no fewer than 8
subsequent readings during induction, and a single application and 2 readings during challenge.
Only completed cases were used to assess sensitization.
3.2.2

Definitions Used for Grading Responses

The symbols found in the scoring scales below were used to express the response observed at thetime of examination:-= No reaction?

= Minimal or doubtful response, slightly different from surrounding normal skin+

= Definite erythema, no edema++= Definite erythema, definite edema+++ = Definite erythema, definite edema and vesiculation
SPECIAL NOTATIONSE= Marked/severe erythemaS= Spreading of reaction beyond patch site (ie, reaction where material did not contact skin)p= Papular response > 50%

pv= Papulovesicular response > 50%

D= Damage to epidermis: oozing, crusting and/or superficial erosionsI= ItchingX= Subject absent

PD = Patch dislodged
NA = Not applied
NP = Not patched (due to reaction achieved)

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-9-

5.0

TKL Study No.

INTERPRETATION

Sensitization is characterized by an acute allergic contact dermatitis. Typical sensitization reactions
begin with an immunologic response in the dermis resulting in erythema, edema formation, andsecondary epidermal damage (vesiculation), sometimes extending beyond the patch site and often
accompanied by itching. Sensitization reactions tend to be delayed. The reaction typically becomes
evident between 24 and 48 hours, peaks at 48-72 hours and subsequently subsides. The reaction isoften greater at 72 hours than at 48 hours. The severity of the reaction is generally greater during thechallenge phase of a Repeated Insult Patch Test (RIPT) than that seen during induction.
Irritant reactions are characterized as a non-immunologic, localized, superficial, exudative,
inflammatory response of the skin due to an externally applied material. The typical initial reaction
does not develop much edema or vesiculation but results in scaling, drying, cracking, oozing,
crusting, and erosions. The reaction is usually sharply delineated, not spreading beyond the patch
site. Irritant reactions are typically evident by 24 hours and diminish over the next 48-72 hours.
Removal of the offending agent results in gradual improvement of the epidermal damage. The
reaction seen at 72 hours is, therefore, less severe than that seen at 48 hours. Finally, the severity of
the reaction experienced in the challenge phase is generally similar to that seen during induction.
If the results of the study indicate the likelihood of sensitization, the recommended practice is torechallenge the subjects who have demonstrated sensitization-like reactions to confirm that thesereactions are, indeed, associated with the product. Our preferred rechallenge procedure involves theapplication of the product to naïve sites, under both occlusive and semi-occlusive patch conditions.
Use of the semi-occlusive patch condition helps to differentiate irritant and sensitization reactions.
Generally speaking, if a product is a sensitizer it will produce a similar reaction under both occlusionand semi-occlusion. Whereas, if the product has caused an irritant reaction, the reactions will be lesspronounced under the semi-occlusive condition.
6.0

PROTOCOL

See Protocol - Appendix V.
7.0

DOCUMENTATION AND RETENTION OF DATA

The case report forms (CRFs) are designed to identify each subject by subject number and initials,
and to record demographics, examination results, adverse events, and end of study status. Originals
or copies of all CRFs, source documents, IRB documents (if required), correspondence, study
reports, and all source data will be kept on hard-copy file for a minimum of 5 years from completionof the study. Storage is maintained either at a TKL facility in a secured room accessible only to TKL
employees, or at an offsite location which provides a secure environment with burglar/fire alarmsystems, camera detection and controlled temperature and humidity. Documentation will beavailable for the sponsor's review on the premises of TKL.

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TKL Study No.

10.0 REFERENCES
Kligman AM. The identification of contact allergens by human assay II. A critique of standard
methods. J Invest Dermatol 1966; 47:369.
Kligman AM. The identification of contact allergens by human assay II. Factors influencing theinduction and measurement of allergic contact dermatitis. J Invest Dermatol 1966; 47:375.
Hardy J. Allergy hypersensitivity in cosmetics. J Soc Cosmet Chem 1973; 24:423.
Marzulli FN, Maibach HI. Contact allergy: predictive testing in man. Contact Dermatitis 1976; 2:1.
Marzulli FN, Maibach HI. Effects of vehicles and elicitation concentration in contact dermatitis
testing I: experimental contact sensitization in humans. Contact Dermatitis 1976; 2:325.
Marzulli FN, Maibach HI. Dermatotoxicology. 4th ed. New York:Hemisphere, 1991.
Fisher AA. 3rd ed. Contact Dermatitis. Philadelphia:Lea & Feiberger, 1986.
Shelanski HA, Shelanski MV. A new technique of human patch tests. Proc Sci Sect Toilet Goods
Assoc 1953; 204:107-110.
Jordan WP, King SF. Related hypersensitivity in families. Contact Dermatitis 1977; 3:19-26.
Kligman AM, Epstein W. Updating the maximization test for identifying contact allergens. Contact
Dermatitis 1975; 1:231-239.
Stotts, J. Planning, conduct and interpretation of human predictive sensitization patch tests. In: Drill
VA, Lazar P, eds. Current Concepts In Cutaneous Toxicity. New York:Academic Press, 1980:4153.

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APPENDIX ISUMMARY TABLESDistributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or QuoteTKL STUDY NO.
TABLE 2: SUMMARY OF SUBJECT DEMOGRAPHICS
ALL ENROLLED SUBJECTS==========================================================================================AGE
N (%) 18 TO 44
N (%) 45 TO 64
N (%) 65 AND UP

39 ( 37.1)
59 ( 56.2)
7 ( 6.7)

MEAN (SD)
MEDIAN
RANGE

48.3 (11.9)
49.3
22.0 TO 69.6

GENDERN (%) MALE
N (%) FEMALE

15 ( 14.3)
90 ( 85.7)

RACE
N (%) CAUCASIAN
N (%) HISPANIC

9 ( 8.6)
96 ( 91.4)==========================================================================================SEE DATA LISTING 2 FOR FURTHER DETAILPROGRAM: DEMOSMY.SAS/USES: DEMOGS/20JAN04:09:08:12

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APPENDIX IIDATA LISTINGSDistributed for Comment Only -- Do Not Cite or QuoteTKL STUDY NO.
DATA LISTING 1: SUBJECT ENROLLMENT AND DISPOSITION
PAGE 1 OF 3
SUBJECT ------------------ STUDY DATES -------------------LASTCOMPLETION DAYS ONNO.
SCREENED
1ST APPLICCHALL APPLICENDEDREADING #STATUS
STUDY==========================================================================================
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2
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4
5
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7
8
9
10
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12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39

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C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
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C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2

C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C

39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39

==========================================================================================
KEY: LAST READING # (I=INDUCTION PHASE, C=CHALLENGE PHASE)COMPLETION STATUS (C=COMPLETED, L=LOST TO FOLLOW-UP, S=VOLUNTARY WITHDRAWAL
V=PROTOCOL VIOLATION, AE=ADVERSE EVENT, O=OTHER)PROGRAM: DISPLIST.SAS/USES: DEMOGS, RESPONSE, FINAL/20JAN04:09:07:57

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DATA LISTING 1: SUBJECT ENROLLMENT AND DISPOSITION
PAGE 2 OF 3
SUBJECT ------------------ STUDY DATES -------------------LASTCOMPLETION DAYS ONNO.
SCREENED
1ST APPLICCHALL APPLICENDEDREADING #STATUS
STUDY==========================================================================================
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
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60
61
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65
66
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70
71
72
73
74
75
76
77
78

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01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04

01/08/04
01/08/04
01/08/04
01/08/04
12/03/03
01/08/04
01/09/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
12/05/03
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04

C2
C2
C2
C2
I0
C2
C3
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
I0
C2
C2
C2
C2
C2

C
C
C
C
S
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
S
C
C
C
C
C

39
39
39
39
3
39
40
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
5
39
39
39
39
39

==========================================================================================
KEY: LAST READING # (I=INDUCTION PHASE, C=CHALLENGE PHASE)COMPLETION STATUS (C=COMPLETED, L=LOST TO FOLLOW-UP, S=VOLUNTARY WITHDRAWAL
V=PROTOCOL VIOLATION, AE=ADVERSE EVENT, O=OTHER)PROGRAM: DISPLIST.SAS/USES: DEMOGS, RESPONSE, FINAL/20JAN04:09:07:57

Distributed for Comment Only -- Do Not Cite or QuoteTKL STUDY NO.
DATA LISTING 1: SUBJECT ENROLLMENT AND DISPOSITION
PAGE 3 OF 3
SUBJECT ------------------ STUDY DATES -------------------LASTCOMPLETION DAYS ONNO.
SCREENED
1ST APPLICCHALL APPLICENDEDREADING #STATUS
STUDY==========================================================================================
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105

12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03

12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03
12/01/03

01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04
01/05/04

01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04
01/08/04

C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2
C2

C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C

39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39
39

==========================================================================================
KEY: LAST READING # (I=INDUCTION PHASE, C=CHALLENGE PHASE)COMPLETION STATUS (C=COMPLETED, L=LOST TO FOLLOW-UP, S=VOLUNTARY WITHDRAWAL
V=PROTOCOL VIOLATION, AE=ADVERSE EVENT, O=OTHER)PROGRAM: DISPLIST.SAS/USES: DEMOGS, RESPONSE, FINAL/20JAN04:09:07:57

Distributed for Comment Only -- Do Not Cite or QuoteTKL STUDY NO.
DATA LISTING 2: SUBJECT DEMOGRAPHICS
PAGE 1 OF 3
SUBJECTNO.
AGE
GENDER
RACE==========================================================================================
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40

44.4
53.1
52.4
56.9
37.5
61.4
39.3
55.9
31.6
41.5
39.3
65.4
53.6
41.1
61.8
56.3
61.7
45.8
60.6
66.3
55.6
30.3
37.0
24.0
68.9
30.2
30.8
58.2
46.9
28.8
38.0
55.0
37.5
51.7
49.3
47.5
39.6
48.5
53.8
36.3

FEMALE
FEMALE
FEMALE
FEMALEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALEMALE
FEMALEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALEHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICCAUCASIAN
HISPANICCAUCASIAN
HISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANIC==========================================================================================PROGRAM: DEMOLIST.SAS/USES: DEMOGS/20JAN04:09:07:58

Distributed for Comment Only -- Do Not Cite or QuoteTKL STUDY NO.
DATA LISTING 2: SUBJECT DEMOGRAPHICS
PAGE 2 OF 3
SUBJECTNO.
AGE
GENDER
RACE==========================================================================================
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80

39.3
57.1
27.4
22.0
64.9
65.1
45.4
38.5
53.1
43.2
56.0
69.6
53.4
31.5
57.7
58.3
49.6
47.6
61.0
62.8
35.7
47.6
58.1
53.1
56.1
38.4
62.2
67.1
34.5
60.4
59.2
52.2
55.4
60.6
52.8
38.4
62.4
49.1
32.3
47.4

MALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALEMALE
FEMALEMALE
FEMALE
FEMALE
FEMALEMALE
FEMALE
FEMALEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALEMALE
FEMALE
FEMALEMALE
FEMALE
FEMALE
FEMALEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALEMALE

HISPANICCAUCASIAN
HISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICCAUCASIAN
HISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICCAUCASIAN
HISPANICHISPANICHISPANICCAUCASIAN
CAUCASIAN
HISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANIC==========================================================================================PROGRAM: DEMOLIST.SAS/USES: DEMOGS/20JAN04:09:07:58

Distributed for Comment Only -- Do Not Cite or QuoteTKL STUDY NO.
DATA LISTING 2: SUBJECT DEMOGRAPHICS
PAGE 3 OF 3
SUBJECTNO.
AGE
GENDER
RACE==========================================================================================
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105

22.6
60.2
67.1
50.9
54.9
57.2
41.5
63.2
50.1
23.9
45.7
39.7
56.6
46.1
39.4
42.0
46.2
41.1
46.5
61.2
35.2
41.6
27.3
32.1
64.0

MALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALE
FEMALEMALE
FEMALE
FEMALE
FEMALE
FEMALEHISPANICHISPANICHISPANICHISPANICHISPANICCAUCASIAN
HISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICHISPANICCAUCASIAN
HISPANICHISPANICHISPANICHISPANICHISPANIC==========================================================================================PROGRAM: DEMOLIST.SAS/USES: DEMOGS/20JAN04:09:07:58

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

Distributed for Comment Only -- Do Not Cite or Quote

APPENDIX III

CLINICAL MATERIAL RECORDDistributed for Comment Only -- Do Not Cite or QuoteTKL RESEARCH, INC.

4 FOREST AVENUE

PARAMUS, NJ 07652

CLINICAL MATERIAL RECORD
PRODUCT ID
CODE

PRODUCT DESCRIPTIONFACIAL MASK/LIGHT BLUE THICK
CLAY

Clay mask with 14.5% kaolin

EXPIRATION
DATE
9/04

TKL Study No. DS107603-5
STORAGECONDITIONS*see code below

RECEIPT

ADDITIONA
L RECEIPT

DATE: 11/25/03

DATE: NAAMOUNT: 7 X

AMOUNT:AMOUNT: NA

DATE:

DATE:

DATE:

AMOUNT:AMOUNT:AMOUNT:A

RETAINEDSAMPLEDATE:GROSS WT.6 OZ
TARE WT.1 OZ
NET WT. 5 OZ.

RETURN TO

RECEIPT RECORDE BY:________________DISPOSITION RECORDED BY___________LOG BOOK PAGE NUMBER:_____________DISPOSITION DATE:

2/10/04

DISPOSITION: Xt RETURNSPONSOR:*STORAGE CONDITIONS:CARRIER:UPS

t DISCARD_

A = AMBIENT (Room Temperature) CONDITIONS
W = WARMER (Temp. Req.______)
R = REFRIGERATED (4-8(C) F = FROZEN (Temp. Req.______)O = OTHER (EXPLAIN): ________________________________________________________________________________________________

STORAGE INFORMATION: Generally, a 20 ml or g sample or a full (pre-packaged) product unit or device will be retained for a period of six months.

Distributed for Comment Only -- Do Not Cite or Quote

ATTAPULGITE

12H

2022 FDA VCRP Raw Data
Paste Masks (mud packs)

BENTONITE
BENTONITE
BENTONITE
BENTONITE
BENTONITE
BENTONITE
BENTONITE
BENTONITE
BENTONITE
BENTONITE
BENTONITE
BENTONITE
BENTONITE
BENTONITE
BENTONITE
BENTONITE
BENTONITE
BENTONITE
BENTONITE
BENTONITE
BENTONITE
BENTONITE
BENTONITE
BENTONITE
BENTONITE
BENTONITE
BENTONITE
BENTONITE
BENTONITE
BENTONITE
BENTONITE
BENTONITE

01C
02A
02D
03A
03B
03C
03D
03E
03F
03G
05G
05I
07A
07B
07C
07F
07I
08E
08F
08G
09A
09C
10A
10E
11D
12A
12C
12D
12F
12H
12I
12J

Other Baby Products
Bath Oils, Tablets, and Salts
Other Bath Preparations
Eyebrow Pencil
Eyeliner
Eye Shadow
Eye Lotion
Eye Makeup Remover
MascaraOther Eye Makeup Preparations
Tonics, Dressings, and Other Hair Grooming Aids
Other Hair Preparations
Blushers (all types)
Face Powders
Foundations
Makeup Bases
Other Makeup Preparations
Nail Polish and Enamel
Nail Polish and Enamel Removers
Other Manicuring Preparations
Dentifrices
Other Oral Hygiene Products
Bath Soaps and Detergents
Other Personal Cleanliness Products
Preshave Lotions (all types)
CleansingFace and Neck (exc shave)
Body and Hand (exc shave)
Moisturizing
Paste Masks (mud packs)
Skin Fresheners
Other Skin Care Preps

2
11
2
1
4
1
1
1
10
1
6
2
2
1
3
1
1
22
1
1
5
3
7
2
1
18
39
3
16
80
1
13

CLAY
CLAY
CLAY
CLAY
CLAY
CLAY
CLAY

02A
03A
03C
03F
05A
05F
05I

Bath Oils, Tablets, and Salts
Eyebrow Pencil
Eye Shadow
MascaraHair Conditioner
Shampoos (non-coloring)
Other Hair Preparations

2
1
8
3
1
2
1

3

Distributed for Comment Only -- Do Not Cite or Quote

CLAY
CLAY
CLAY
CLAY
CLAY
CLAY
CLAY
CLAY
CLAY
CLAY
CLAY
CLAY
CLAY
CLAY
CLAY

07A
07B
07C
07E
07F
09A
09C
10A
10B
12A
12C
12D
12F
12H
12J

Blushers (all types)
Face Powders
Foundations
Lipstick
Makeup Bases
Dentifrices
Other Oral Hygiene Products
Bath Soaps and Detergents
Deodorants (underarm)
CleansingFace and Neck (exc shave)
Body and Hand (exc shave)
Moisturizing
Paste Masks (mud packs)
Other Skin Care Preps

3
1
1
6
1
1
3
4
2
2
10
1
1
4
1

FULLER'S EARTH
FULLER'S EARTH
FULLER'S EARTH
FULLER'S EARTH

05G
10A
12H
12J

Tonics, Dressings, and Other Hair Grooming Aids
Bath Soaps and Detergents
Paste Masks (mud packs)
Other Skin Care Preps

1
1
6
1

HECTORITEHECTORITEHECTORITEHECTORITEHECTORITEHECTORITEHECTORITEHECTORITEHECTORITEHECTORITEHECTORITEHECTORITEHECTORITEHECTORITEHECTORITEHECTORITEHECTORITEHECTORITEHECTORITEHECTORITE

01B
03B
03C
03F
03G
05A
05E
05I
06D
07B
07C
07D
07F
07I
08G
12A
12C
12G
12H
12J

Baby Lotions, Oils, Powders, and Creams
Eyeliner
Eye Shadow
MascaraOther Eye Makeup Preparations
Hair Conditioner
Rinses (non-coloring)
Other Hair Preparations
Hair Shampoos (coloring)
Face Powders
Foundations
Leg and Body Paints
Makeup Bases
Other Makeup Preparations
Other Manicuring Preparations
CleansingFace and Neck (exc shave)Night
Paste Masks (mud packs)
Other Skin Care Preps

1
7
1
8
1
3
1
1
1
1
1
1
1
1
1
7
5
3
4
1

Distributed for Comment Only -- Do Not Cite or QuoteILLITEILLITEILLITEILLITEILLITEILLITEILLITEILLITEILLITEILLITEILLITEILLITEILLITE

02A
02D
05F
05G
07B
07C
09A
10A
12A
12C
12F
12H
12J

Bath Oils, Tablets, and Salts
Other Bath Preparations
Shampoos (non-coloring)
Tonics, Dressings, and Other Hair Grooming Aids
Face Powders
Foundations
Dentifrices
Bath Soaps and Detergents
CleansingFace and Neck (exc shave)
Moisturizing
Paste Masks (mud packs)
Other Skin Care Preps

KAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLIN

01B
02A
02D
03A
03B
03C
03F
03G
04C
05A
05B
05F
05G
05H
05I
06F
06G
07A
07B
07C
07D
07E
07F
07G
07H
07I
08A
08E
08G

Baby Lotions, Oils, Powders, and Creams
Bath Oils, Tablets, and Salts
Other Bath Preparations
Eyebrow Pencil
Eyeliner
Eye Shadow
MascaraOther Eye Makeup Preparations
Powders (dusting and talcum, excluding aftershave talc)
Hair Conditioner
Hair Spray (aerosol fixatives)
Shampoos (non-coloring)
Tonics, Dressings, and Other Hair Grooming Aids
Wave Sets
Other Hair Preparations
Hair Lighteners with Color
Hair Bleaches
Blushers (all types)
Face Powders
Foundations
Leg and Body Paints
Lipstick
Makeup Bases
RougesMakeup Fixatives
Other Makeup Preparations
Basecoats and Undercoats
Nail Polish and Enamel
Other Manicuring Preparations

1
1
1
2
2
1
1
1
6
18
2
17
6
1
17
1
6
6
137
29
23
5
7
1
17
14
1
7
1
12
39
47
35
3
134
3
2
1
12
1
7
1

Distributed for Comment Only -- Do Not Cite or Quote

KAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINKAOLINITEKAOLINITEKAOLINITEKAOLINITEKAOLINITEKAOLINITEKAOLINITE

09A
10A
10B
10E
11B
11F
11G
12A
12C
12D
12F
12G
12H
12I
12J
11C
02C
07C
10A
12A
12F
12H
12J

Dentifrices
Bath Soaps and Detergents
Deodorants (underarm)
Other Personal Cleanliness Products
Beard Softeners
Shaving Soap
Other Shaving Preparation Products
CleansingFace and Neck (exc shave)
Body and Hand (exc shave)
Moisturizing
Night
Paste Masks (mud packs)
Skin Fresheners
Other Skin Care Preps
Mens Talcum
Bath Capsules
Foundations
Bath Soaps and Detergents
Cleansing
Moisturizing
Paste Masks (mud packs)
Other Skin Care Preps

16
11
7
9
1
1
1
84
73
14
29
3
153
3
59
1
1
1
4
1
1
2
1

MONTMORILLONITE
MONTMORILLONITE
MONTMORILLONITE
MONTMORILLONITE
MONTMORILLONITE
MONTMORILLONITE
MONTMORILLONITE
MONTMORILLONITE
MONTMORILLONITE
MONTMORILLONITE
MONTMORILLONITE
MONTMORILLONITE
MONTMORILLONITE
MONTMORILLONITE
MONTMORILLONITE
MONTMORILLONITE
MONTMORILLONITE

02A
02D
03A
03E
05A
05F
05G
07C
09A
10A
10E
12A
12C
12D
12F
12H
12J

Bath Oils, Tablets, and Salts
Other Bath Preparations
Eyebrow Pencil
Eye Makeup Remover
Hair Conditioner
Shampoos (non-coloring)
Tonics, Dressings, and Other Hair Grooming Aids
Foundations
Dentifrices
Bath Soaps and Detergents
Other Personal Cleanliness Products
CleansingFace and Neck (exc shave)
Body and Hand (exc shave)
Moisturizing
Paste Masks (mud packs)
Other Skin Care Preps

1
1
1
1
1
4
1
1
1
6
3
15
8
3
6
16
6