Amended Safety Assessment of Mentha Piperita (Peppermint) - Derived Ingredients As Used in Cosmetics

Amended Safety Assessment of
Mentha Piperita (Peppermint)-derived Ingredients as Used in

Cosmetics
Status: Re-review for Panel Review

Release Date: March 17, 2017
Panel Date: April 10-11, 2017
The 2017 Cosmetic Ingredient Review Expert Panel members are: Chair, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V.
Belsito, M.D.; Ronald A. Hill, Ph.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; James G. Marks, Jr., M.D.; Ronald
C. Shank, Ph.D.; Thomas J. Slaga, Ph.D.; and Paul W. Snyder, D.V.M., Ph.D. The CIR Director is Lillian J. Gill, D.P.A.
This report was prepared by Wilbur Johnson, Jr., M.S., Senior Scientific Analyst., Bart Heldreth, Ph.D., Chemist, and Ivan
Boyer, Ph.D., Toxicologist.
© Cosmetic Ingredient Review

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Memorandum
To: CIR Expert Panel Members and Liaisons

From: Wilbur Johnson, Jr.
Senior Scientific Analyst
Date: March 17, 2017
Subject: Re-review of Mentha Piperita-derived Ingredients
The safety of the following cosmetic ingredients has been reviewed by the Cosmetic Ingredient Review (CIR) Expert Panel
(Panel), and a final report with a conclusion stating that these ingredients are safe as used in cosmetic formulations was
published in 2001: Mentha Piperita (Peppermint) Oil, Mentha Piperita (Peppermint) Leaf Extract, Mentha Piperita
(Peppermint) Leaf, and Mentha Piperita (Peppermint) Leaf Water. The conclusion also contains a statement indicating that
the concentration of pulegone in these ingredients should not exceed 1%.
The current safety assessment is a re-review of the 4 Mentha Piperita (Peppermint)-derived ingredients, and is inclusive of
safety test data that have become available since the final report was issued. Safety test data and the discussion from the
published final report are italicized in the report text. It should be noted that most of the data in the 2001 report are on
Mentha Piperita (Peppermint) Oil, and that the Panel determined that Mentha Piperita (Peppermint) Oil is considered to
present the "worst case scenario" because of its many constituents and that data on the oil were considered relevant to the
entire group of ingredients. With this in mind, the Panel will need to determine whether or not this opinion remains valid.
Furthermore, safety test data on Mentha Piperita (Peppermint) Leaf, Mentha Piperita (Peppermint) Leaf Extract, and
Mentha Piperita (Peppermint) Leaf Water are not included in the 2001 report, but the re-review document contains the
following data for the Panel’s consideration: Mentha Piperita (Peppermint) Leaf Extract (skin penetration enhancement and
hepatotoxicity), Mentha Piperita (Peppermint) Leaf (nephrotoxicity), and updated use concentration data and unpublished
human skin irritation, sensitization, and ocular irritation data on Mentha Piperita (Peppermint) Leaf Water
(pepper042017data1, pepper042017data1a, and pepper042017data 2) that were received from the Council.
Taking into consideration the Panel’s limit on pulegone in these ingredients as stated in the 2001 report, data from a
National Toxicology Program (NTP) carcinogenicity study on pulegone that was published in 2012 are also included for
the Panel’s consideration.
In addition to the 4 ingredients that are the subject of this re-review, it should be noted that monographs on the following
additional 6 Mentha piperita-derived ingredients are included in the International Cosmetic Ingredient Dictionary and
Handbook (Dictionary): Mentha Piperita (Peppermint) Extract, Mentha Piperita (Peppermint) Flower/Leaf/Stem Extract,
Mentha Piperita (Peppermint) Flower/Leaf/Stem Water, Mentha Piperita (Peppermint) Leaf Cell Extract, Mentha Piperita
(Peppermint) Leaf Juice, and Mentha Piperita (Peppermint) Meristem Cell Culture. These ingredients, along with the
Dictionary definitions and functions, are included in Table 1 (in bold print) of the re-review document. The Panel is being
asked to determine whether the Panel’s safety assessment of Mentha piperita-derived ingredients should be expanded to
include the additional 6 ingredients.
Included in this package for your review is the Re-review document (pepper042017rep), the CIR report history
(pepper042017hist), Literature search strategy (pepper042017strat), Ingredient Data profile (pepper042017prof), 2017
FDA VCRP data (pepper042017FDA), Use concentration data received from the Council (pepper042017data1 and
__________________________________________________________________________________________
1620 L Street, NW Suite 1200, Washington, DC 20036
(Main) 202-331-0651 (Fax) 202-331-0088
(Email) cirinfo@cir-safety.org (Website) www.cir-safety.org
pepper042017data1a), Human skin irritation, sensitization, and ocular irritation data received from the Council
(pepper042017data2), and the 2001 published Final Report on Mentha Piperita-derived ingredients (pepper042017prev).
After reviewing the available data, the Panel needs to determine whether the final report on Mentha Piperita-derived
ingredients should be reopened at this meeting.
__________________________________________________________________________________________
1620 L Street, NW Suite 1200, Washington, DC 20036
(Main) 202-331-0651 (Fax) 202-331-0088
(Email) cirinfo@cir-safety.org (Website) www.cir-safety.org
Distributed for comment only -- do not cite or quote
Public Comment CIR Expert Panel Re-Review Rpt Status
New Data; or
announce 15 years OR request
since last
review
Re-review
to Panel
PRIORITY LIST April 2017
Are new data cause to reopen? 4 ingredients in original

report.
5 proposed add-ons.
YES
NO
DRAFT AMENDED
DAR REPORT* Are new ingredients
appropriate for
inclusion/re-open?
Table
Table IDA TAR
Yes No
IDA Notice IDA

RE-REVIEW Admin Book
SUMMARY
DRAFT TENTATIVE
Draft TAR
AMENDED REPORT
60 day public comment period
Table
Table
Tentative
Amended Report
Issue
TAR
Draft FAR DRAFT FINAL

60 day Public comment period AMENDED REPORT
Table
Table Different Conclusion
Final Amended Issue

PUBLISH Report FAR
*If Draft Amended Report (DAR) is available, the Panel may choose to review; if not, CIR staff prepares DAR for Panel Review.
CIR History of:
Mentha Piperita-derived Ingredients
A Final Report with a conclusion stating that the following ingredients are safe as used in cosmetic formulations was
issued at the September 10-11, 1998 CIR Expert Panel meeting and published in 2001: Mentha Piperita
(Peppermint) Oil, Mentha Piperita (Peppermint) Leaf Extract, Mentha Piperita (Peppermint) Leaf, and Mentha
Piperita (Peppermint) Leaf Water. The conclusion also contains a statement indicating that the concentration of
pulegone in these ingredients should not exceed 1%.
Re-review document, Teams/Panel: April 10-11, 2017
Use concentration data on Mentha Piperita-derived ingredients and human skin irritation, sensitization, and ocular
irritation data on Mentha Piperita (Peppermint) Leaf Water that were received from the Council have been added to
the report text.
Epidemiology Human
Studies
Reports
Human-Oral
Case
Human-Dermal
X
X
Studies
Clinical
Human-
Dermal/Oral
X
0/X
Irritation
Animal/Human
Ocular
In Vitro
Sensitization*/
Phototoxicity*
Human
X/0
X/0
Dermal
Animal
0/X
Dermal Animal/Human
X/X
0/X
Irritation*
\Mentha piperita-derived Ingredients Data Profile for April 10 -11 , 2017 Panel – Wilbur Johnson
Other Relevant In Vivo-Animal

Studies
X
In Vitro
Carcinogenicity In Vivo
X
Genotoxicity In Vitro
X
In Vivo
X
DART
th
In Vitro
th
Chronic
Toxicity Animal
Sub-Chronic Animal
X
Toxicity
Short-Term Animal
X
Toxicity
Animal-Inhalation
Acute Toxicity
Animal-Oral
X
Animal-Dermal
X
Human-Oral
Animal-IV
ADME
Animal-Oral
Animal-Dermal
In Vitro-Human
Dermal
Penetration In Vitro-Animal
X
Enhancement
Nail In Vitro-Human
Penetration
In Vivo-Human
Penetration
X = data; 0 = no data*
Dermal
In Vitro-Human
X
In Vivo -Animal
Safety Data
X
Available?
Used in
X
Cosmetics?
(Peppermint)
(Peppermint)
(Peppermint)
(Peppermint)
Leaf Extract
Leaf Water
Piperita
Piperita
Piperita
Piperita
Mentha
Mentha
Mentha
Mentha
Leaf
Oil
[Mentha Piperita-derived Ingredients (5/16/2016; 2/5/2017]
Ingredient CAS # InfoBase SciFinder PubMed TOXNET FDA EU ECHA IUCLID SIDS HPVIS NICNAS NTIS NTP WHO FAO FEMA Web
Mentha Piperita 8006-90-4 1/1 164/14 164/11 165/11 1 0 0 0 0 0 0 0 0 0 0 0
(Peppermint) Oil 84082-70-2
Mentha Piperita 84082-70-2 1./1 4/1 1/1 5/2 1 0 0 0 0 0 0 0 0 0 0 0
(Peppermint) Leaf Extract
Mentha Piperita 1/1 197/19 10/3 34/4 1 0 0 0 0 0 0 0 0 0 0 0
(Peppermint) Leaf
Mentha Piperita 84082-70-2 1/1 1/1 2/1 4/1 1 0 0 0 0 0 0 0 0 0 0 0
(Peppermint) Leaf Water
Search Strategy
[document search strategy used for SciFinder, PubMed, and Toxnet]
[identify total # of hits /# hits that were useful or examined for usefulness]
LINKS
InfoBase (self-reminder that this info has been accessed; not a public website) - http://www.personalcarecouncil.org/science-safety/line-infobase
ScfFinder (usually a combined search for all ingredients in report; list # of this/# useful) - https://scifinder.cas.org/scifinder
PubMed (usually a combined search for all ingredients in report; list # of this/# useful) - http://www.ncbi.nlm.nih.gov/pubmed
Toxnet databases (usually a combined search for all ingredients in report; list # of this/# useful) – https://toxnet.nlm.nih.gov/ (includes Toxline; HSDB; ChemIDPlus; DAR;
IRIS; CCRIS; CPDB; GENE-TOX)
FDA databases – http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm (CFR); then,

list of all databases: http://www.fda.gov/ForIndustry/FDABasicsforIndustry/ucm234631.htm; then,
http://www.accessdata.fda.gov/scripts/fcn/fcnnavigation.cfm?rpt=eafuslisting&displayall=true (EAFUS);
http://www.fda.gov/food/ingredientspackaginglabeling/gras/default.htm (GRAS);
http://www.fda.gov/food/ingredientspackaginglabeling/gras/scogs/ucm2006852.htm (SCOGS database);
http://www.accessdata.fda.gov/scripts/fdcc/?set=IndirectAdditives (indirect food additives list);
http://www.fda.gov/Drugs/InformationOnDrugs/default.htm (drug approvals and database);
http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM135688.pdf (OTC ingredient list);
http://www.accessdata.fda.gov/scripts/cder/iig/ (inactive ingredients approved for drugs)
EU (European Union); check CosIng (cosmetic ingredient database) for restrictions and SCCS (Scientific Committee for Consumer Safety) opinions -
http://ec.europa.eu/growth/tools-databases/cosing/
ECHA (European Chemicals Agency – REACH dossiers) – http://echa.europa.eu/information-on-chemicals;jsessionid=A978100B4E4CC39C78C93A851EB3E3C7.live1
IUCLID (International Uniform Chemical Information Database) - https://iuclid6.echa.europa.eu/search
OECD SIDS documents (Organisation for Economic Co-operation and Development Screening Info Data Sets)- http://webnet.oecd.org/hpv/ui/Search.aspx
HPVIS (EPA High-Production Volume Info Systems) - https://ofmext.epa.gov/hpvis/HPVISlogon
NICNAS (Australian National Industrial Chemical Notification and Assessment Scheme)- https://www.nicnas.gov.au/
NTIS (National Technical Information Service) - http://www.ntis.gov/
NTP (National Toxicology Program ) - http://ntp.niehs.nih.gov/
WHO (World Health Organization) technical reports - http://www.who.int/biologicals/technical_report_series/en/
FAO (Food and Agriculture Organization of the United Nations) - http://www.fao.org/food/food-safety-quality/scientific-advice/jecfa/jecfa-additives/en/ (FAO);
FEMA (Flavor & Extract Manufacturers Association) - http://www.femaflavor.org/search/apachesolr_search/
Web – perform general search; may find technical data sheets, published reports, etc
ECETOC (European Center for Ecotoxicology and Toxicology Database) - http://www.ecetoc.org/
Botanical Websites, if applicable

Dr. Duke’s https://phytochem.nal.usda.gov/phytochem/search
Taxonomy database - http://www.ncbi.nlm.nih.gov/taxonomy
GRIN (U.S. National Plant Germplasm System) - https://npgsweb.ars-grin.gov/gringlobal/taxon/taxonomysimple.aspx
Sigma Aldrich plant profiler http://www.sigmaaldrich.com/life-science/nutrition-research/learning-center/plant-profiler.html
Fragrance Websites, if applicable

IFRA (International Fragrance Association) – http://www.ifraorg.org/
RIFM (the Research Institute for Fragrance Materials) should be contacted

Day 2 of the June 3-4, 1996 CIR Expert Panel Meeting
Peppermint Oil
Dr. Schroeter noted that an informal data request on Peppermint Oil was issued at the March 4-5, 1996 Panel
meeting. With the exception of the RIFM (Research Institute For Fragrance Materials) monograph on Peppermint
Oil that was received, there was no response to the informal data request that was issued. Thus, the Panel voted
unanimously in favor of issuing an Insufficient Data Announcement on Peppermint Oil with the following data
requests:
(1) Concentration of use

(2) UV absorption; if significantly absorbed in the UVA or UVB range,
then a photosensitization study may be needed
(3) Rate of dermal absorption (of either peppermint oil or its principal
component, menthol); if significantly absorbed, then a 28-day dermal
toxicity study and reproductive and developmental toxicology data are
needed
(4) Human dermal irritation and sensitization
The Panel also requested that the present review be expanded to include literature citations on menthol.
Day 2 of the December 16-17, 1996 CIR Expert Panel Meeting
Peppermint (Mentha piperita) Oil, Peppermint (Mentha piperita) Extract,

and Peppermint (Mentha piperita) Leaves
Dr. Belsito noted that an Insufficient Data Announcement on this group of ingredients was issued at the June
3-4, 1996 Panel meeting. Also, in considering the data on menthol that were incorporated into the present report
after this announcement was issued, the Belsito Team determined that the available data are still insufficient for
evaluating the safety of these three ingredients. Dr. Belsito stated his Team=s data needs as follows: (1)
Concentration of use; (2) Impurities of cosmetic grade Peppermint Oil, specifically pulegone; or, in the absence of
impurities data, (3) a 28-day dermal toxicity study on cosmetic grade Peppermint Oil.
Dr. Schroeter recalled that the potential need for 28-day dermal toxicity data is expressed in item #2 of the
Insufficient Data Announcement as follows: Rate and extent of dermal absorption of Peppermint Oil or menthol; if
there is significant skin penetration, then both a 28-day dermal toxicity study to assess general skin and systemic
toxicity and a reproductive and developmental toxicity study are needed.
Drs. Shank and Schroeter noted that if the systemic toxicity resulting from the dermal route is the same (or
less) compared to that resulting from oral exposure, then a dermal reproductive and developmental toxicity test will
not be needed.
Dr. Klaassen wanted to know which toxic effects observed in oral studies were of concern.
Dr. Carlton noted that spongiform encephalopathy was observed in oral toxicity studies, and that the impurity
pulegone was probably responsible for this finding.
Dr. Andersen brought to the Panel=s attention that an oral reproductive and developmental toxicity study on
menthol is included in the present report on Peppermint Oil. He noted that menthol is a significant component of
Peppermint Oil.
Regarding the issue of exposure, especially regarding pulegone as a contaminant of Peppermint Oil, Dr.
Bailey said that the Panel may want to consider more accurate skin penetration data relative to Peppermint Oil
and/or the contaminant.
Dr. Andersen said that the Panel=s concern about the safety of cosmetic grade Peppermint Oil seems to be
based on the assumption that it may contain the impurity, pulegone. He also said that if pulegone is not detected in
the impurities analysis, then there should be no concern about its absorption and, also, no need for a 28-day dermal
toxicity study.
The Panel voted unanimously in favor of issuing a Tentative Report with an insufficient data conclusion.
The data needed in order for the Panel to complete its safety assessment of Peppermint Oil, Peppermint Extract, and
Peppermint Leaves are listed in the discussion section of the report as follows:

(2) Impurities (specifically pulegone) in cosmetic grade Peppermint (Mentha
Piperita) Oil, Peppermint (Mentha Piperita) Extract, and Peppermint (Mentha
Piperita) Leaves or in the absence of impurities data, a 28-day dermal toxicity
study using cosmetic grade ingredients. (Note: If changes found following
dermal exposure are the same as those reported in existing oral-dosing
studies, then there will be no need for reproductive and developmental toxicity
studies; if the results are not similar, then there may be a need for dermal
reproductive and developmental toxicity studies.)
Day 2 of the June 5-6, 1997 CIR Expert Panel Meeting – Full Panel
Peppermint (Mentha Piperita) Oil

Peppermint (Mentha Piperita) Extract
Peppermint (Mentha Piperita) Leaves
Dr. Schroeter noted that the Panel issued a Tentative Report with an insufficient data conclusion at the
December 16-17, 1996 Panel meeting. The data needed in order for the Panel to complete its safety assessment
were stated as follows:

(2) Impurities (especially pulegone) in cosmetic grade Peppermint
(Mentha Piperita) Oil, Peppermint (Mentha Piperita) Extract, and
Peppermint (Mentha Piperita) Leaves or in the absence of impurities
data, a 28-day dermal toxicity study using cosmetic grade ingredients.
(Note: If changes found following dermal exposure are the same as
those reported in existing oral-dosing studies, then there will be no need
for reproductive and developmental toxicity studies; if the results are not
similar, then there may be a need for dermal reproductive and develop-
mental toxicity studies.)
Dr. Schroeter said that, in response to the Tentative Report, the Panel received impurities data on
Peppermint Oil (pulegone detected at concentrations of 1 to 4%) and data indicating use concentrations of
Peppermint Oil in the range of 0.02 to 3.0%. Dr. Schroeter noted that, based on the impurities analysis, his Team
determined that pulegone is at a level that is not significantly toxic. Thus, the Schroeter Team concluded that
Peppermint (Mentha Piperita) Oil, Peppermint (Mentha Piperita) Extract, and Peppermint (Mentha Piperita) Leaves
are safe as used in cosmetics.
Dr. Bronaugh noted that the levels of the impurity, pulegone reported by industry fall within the range of the
short-term oral toxicity on pages 15-16 of the Tentative Report. The Peppermint Oil sample tested contained 1.7%
pulegone, and the no-effect-level for Peppermint Oil in this study was 10 mg/kg body weight.
Dr. Bronaugh also noted that FDA has done an exposure assessment based on some of the new data
submitted on a body splash lotion containing 0.2% Peppermint Oil. He said that if one assumes whole-body
application of the lotion and 100% absorption (since there are no absorption data on Peppermint Oil), approximately
1 mg of Peppermint Oil per day is absorbed. He also said that the use of a 100-fold safety factor reduces the 10
mg/kg no-effect-level to 0.1 mg/kg. Therefore, without knowing absorption, it is possible that as much as 1 mg of
Peppermint Oil/kg will be absorbed if the body splash lotion is applied over the entire body. Dr. Bronaugh noted
that there is some concern over the use of Peppermint Oil in cosmetics, not knowing the extent of its dermal
absorption.
Dr. Bailey said that Dr. Bronaugh=s comments become particularly relevant if one considers that the body
splash lotion may be used on infants and children. Dr. Bailey reiterated that a no-effect-level has been determined,
and acknowledged that an extremely conservative exposure estimate was used in the calculation. However, he noted
that even if one assumes 10% area and 50% absorption, the safety factor is 180. According to Dr. Bailey, this means
that an area in which safety becomes more of a question is being approached. Furthermore, he said that this
becomes even more relevant when infants and children are taken into consideration.
Dr. McEwen asked Dr. Bronaugh if, based on his calculation, 1 mg of Peppermint Oil would be applied to
the body.
Dr. Bronaugh said that 1 mg of Peppermint Oil/kg would be absorbed per day (by a human) by applying the
body splash lotion that reportedly contains 0.2% Peppermint Oil. He also said that 68 mg/day would be absorbed,
and, if one divides this by a 60 kg person, this translates into 1.12 mg/kg/day absorption. This estimate assumes 2
mg/cm2 application over the whole body.
Dr. Andersen wanted to know if the concerns expressed by Drs. Bailey and Bronaugh relate to Peppermint
Oil or the pulegone component.
Dr. Bronaugh said that the theory is based on Peppermint Oil. However, he noted that Peppermint Oil tested
in the study by Thorup et al., 1983a (pp.15-16 of Tentative Report) contains 1.7% pulegone.
Dr. McEwen said that it would probably be difficult, if not impossible, to apply a body splash at a
concentration of 2 mg/cm2.
Dr. Bronaugh said that 2 mg is approximately 2 l, which is a small amount.
Dr. Schroeter said that it takes an ounce of content, 28 ml, to cover a total body (for an average adult, this is
actually 1.7 m2). With this in mind, he said that he is also concerned about the data.
Dr. Bergfeld said that the Panel has the option of tabling the Tentative Report on Peppermint Oil, placing it
in Teams for further discussion.
The Panel voted unanimously in favor of tabling the Tentative Report until the September 22-23, 1997 Panel
meeting.
Dr. Bergfeld asked the Panel to elaborate on additional information that would be needed to address Dr.
Bronaugh=s concerns regarding Peppermint Oil/pulegone exposure.
Dr. Schroeter said that the Panel needs to review the data on which FDA=s calculations are based, as well as
the actual calculations.
Dr. Bailey noted that the no-effect-level of 10 mg/kg/day for Peppermint Oil was taken from the Tentative
Report. He added that an ADI of 0.1 mg/kg/day has been reported for Peppermint Oil.
Dr. Bailey stated that the Panel will be provided with a copy of FDA=s calculations.
Dr. Bergfeld said that because the extent of percutaneous absorption of Peppermint Oil is not known, it
would be appropriate for the Panel to informally request any available absorption studies on Peppermint Oil that
have not been submitted to CIR.
Day 2 of the September 22-23, 1997 CIR Expert Panel Meeting
Peppermint (Mentha Piperita) Oil,

Peppermint (Mentha Piperita) Extract,
and Peppermint (Mentha Piperita) Leaves
At the June 5-6, 1997 Panel meeting, The Panel voted unanimously in favor of tabling the Tentative Report
(insufficient data conclusion issued at December 1996 Panel meeting) on this group of ingredients until the
September 22-23, 1997 Panel meeting. [Note: Prior to the June 5-6, 1997 review, the concentration of use and
impurities data requested by the Panel were received.] This action resulted from statements made by Drs. Bailey
and Bronaugh relating to the fact that FDA had done an exposure assessment of Peppermint Oil based on the
concentration of use data supplied by industry. In this assessment (made available for present meeting), a
concentration of 0.2% (reported use concentration in a body splash) was selected, and 100% absorption was
assumed per whole body application (2 mg/cm2). This translated into the absorption of 34 mg Peppermint Oil/day
(0.6 mg/kg/day exposure for a 60 kg person).
It was also noted in the exposure assessment that an acceptable daily intake (ADI) of 0.2 mg/kg body weight
day for menthol (major constituent of Peppermint Oil) was derived by the Joint Expert Committee on Food
Additives, and that the ADI calculated using the data in the CIR report on Peppermint Oil was 0.1 mg/kg body
weight/day for this ingredient.
During deliberations at the present meeting, the Panel expressed concern over oral-dosing studies on
Peppermint Oil in which cyst-like spaces in the cerebellum of rats were reported, and the difficulty in interpreting
these study results (due to inconsistent findings when results were compared). Though the lesions appeared to
depend on the pulegone content (a greater NOAEL [no observable adverse effects level] was reported in a 90-day
oral toxicity study in which Peppermint Oil containing 1.1% pulegone was tested, compared to a 28-day oral toxicity
study in which Peppermint Oil containing 1.7% pulegone was tested), no definitive conclusion could be made.
Given the results for Peppermint Oil containing pulegone in short-term and subchronic oral toxicity studies,
Dr. Belsito recommended that pulegone, as an impurity, should be limited to a concentration of 1% in Peppermint
Oil, Peppermint Extract, and Peppermint Leaves.
Dr. Bronaugh noted that the toxicity of menthol is similar to that of pulegone.
The Panel also expressed concern over menthol, major component of Peppermint Oil. In the absence of
dermal absorption studies on Peppermint Oil, it was noted that its absorption is expected to be rapid, like menthol.
Furthermore, there was concern that this rapid rate of absorption may induce systemic toxicity that was not observed
following oral exposure. Thus, the Panel decided to limit the cosmetic use of Peppermint Oil and other ingredients
in this review such that the menthol content would not exceed the ADI (0.2 mg/kg/day for menthol) that was
established by the World Health Organization.
The Panel agreed that the inconsistencies between results from short-term and subchronic oral toxicity
studies on Peppermint Oil should be addressed in the report discussion, along with the Panel=s basis for using the
ADI for menthol in its safety assessment.
The Panel voted unanimously in favor of issuing a Revised Tentative Report with the following conclusion:
On the basis of the available data, the CIR Expert Panel concludes that Peppermint (Mentha Piperita) Oil,
Peppermint (Mentha Piperita) Extract, and Peppermint (Mentha Piperita) Leaves are safe for use in cosmetic
formulations at levels such that the menthol content does not exceed the ADI of 0.2 mg/kg/day. The pulegone level
should not exceed 1% in these ingredients.
Day 2 of the March 19-20, 1998 CIR Expert Panel Meeting

Dr. Schroeter said that questions relating to the menthol component of Peppermint Oil remain. One of the
questions raised by the Panel related to whether it would be logical to make an exception in the conclusion regarding
the concentration of menthol, that it not exceed the ADI (average daily intake) of 0.2 mg/kg/day. Dr. Schroeter
noted that his Team determined that there is no need for any specific limitation on menthol in either the report
discussion or conclusion. He said that the issue of the dermal absorption of menthol may be managed by explaining
in the discussion that the amount of menthol that may be absorbed through the skin is safe, if compared to the same
amount in Peppermint Oil that is absorbed from the gastrointestinal tract, which is already considered a safe amount.
Based on the preceding comments, Dr. Schroeter said that the statement in the report discussion that
mentions the ADI of 0.2 mg/kg/day for menthol will be replaced with statements based on the following: The
dermal absorption of menthol will be no greater than that of oral Peppermint Oil. The clinical data will provide
adequate evidence of safety at current concentrations of use [that is, since oral data are adequate for demonstrating
that menthol is equal to or not greater than that absorbed through the skin].
Dr. Bailey wanted to know if clinical data (ingestion data) obviate the need for dermal absorption data.
Dr. Shank said that for systemic toxicity, the oral data are sufficient, because it is believed that the extent of
absorption through the skin would not be any greater than the absorption through the GI tract and that the Afirst pass@
consideration is not important. He noted that Afirst pass@ effects were considered, and it was determined that the
available data are sufficient. Dr. Shank also said that as far as skin effects are concerned, clinical data support the
safety of current concentrations of use.
Dr. Bergfeld confirmed with Dr. Schroeter that the substance of Dr. Shank=s explanation will be included in
the report discussion.
Dr. Schroeter said that Dr. Shank=s explanation is logical, and, therefore, does not limit the concentration.
Dr. McEwen said that it is not that Afirst pass@ kinetics are not the primary argument, but, taking this into
consideration, there was a sufficient justification for considering the oral doses administered and assuming that the
clinical epidermal doses would not sufficiently increase systemic toxicity.
Dr. Andersen recalled that at the last Panel meeting, FDA expressed concern over a calculation that
compared the reported concentrations of menthol that could be present in levels of Peppermint Oil that were actually
reported to be used. He said that based on that combination of the concentration of Peppermint Oil and the
concentration of menthol in it, it was concluded that those levels approached the reported toxicity that was actually
included in the CIR report. Dr. Andersen asked FDA for further comments.
Dr. Bronaugh said that because a limitation on the concentration of pulegone is included in the report
discussion, one would think that this is adequate.
Dr. Bergfeld said that the revisions in both the report discussion and conclusion need to be discussed and that
the Panel needs to vote on the new conclusion. She also said that the Panel needs to discuss the merit of the
conclusion and determine whether the present report needs to be reissued as a Tentative Report.
Dr. Bergfeld asked if there was any further discussion regarding the current revised conclusion and the
editorial changes in the report discussion that are being considered. Seeing that there was no further discussion, she
called for the vote.
The old conclusion that is being revised reads as follows: On the basis of the available data, the CIR Expert
Panel concludes that Peppermint (Mentha Piperita) Oil, Peppermint (Mentha Piperita) Extract, Peppermint (Mentha
Piperita) Leaves, and Peppermint (Mentha Piperita) Water are safe for use in cosmetic formulations at levels such
that the menthol content does not exceed the ADI of 0.2 mg/kg/day. The Pulegone level should not exceed 1% in
these ingredients.
The Panel voted unanimously in favor of issuing a Revised Tentative Report with the following revised
conclusion: On the basis of the available data, the CIR Expert Panel concludes that Peppermint (Mentha Piperita)
Oil, Peppermint (Mentha Piperita) Extract, Peppermint (Mentha Piperita) Leaves, and Peppermint (Mentha Piperita)
Water are safe as used in cosmetic formulations. The concentration of pulegone in these ingredients should not
exceed 1%.
Day 2 of the September 10-11, 1998 CIR Expert Panel Meeting

Dr. Schroeter stated that his Team concluded that these ingredients are safe as used in cosmetic formulations,
and that the concentration of pulegone in each should not exceed 1.0%. The restriction on pulegone is based on the
sensitization potential of this impurity.
Additionally, Dr. Schroeter noted that the percutaneous absorption of other chemicals is enhanced in the
presence of Peppermint Oil, and that this issue should be addressed in the report discussion. He suggested that the
statement addressing this issue in the CIR report on Peanut Oil should be incorporated into the report on Peppermint
Oil.
Dr. Belsito read the following statement from the report on Peanut Oil, relating it to Peppermint Oil: The
Panel noted the evidence that Peppermint Oil can enhance penetration. Formulators are cautioned that this enhanced
penetration can affect the use of other ingredients whose safety assessment was based on their lack of absorption.
Dr. Bergfeld recommended inclusion of the preceding statement, with any necessary modifications, in the
Peppermint Oil report discussion.
Dr. Belsito recommended that it be clarified in the last sentence of the report discussion that use of
Peppermint Oil at a concentration of  3% in rinse-off formulations and  0.2% in leave-on formulations, coupled
with the restriction of pulegone to  1%, alleviates the Panel=s concern about pulegone toxicity.
The Panel voted unanimously in favor of issuing a Final Report with the following conclusion: On the basis
of the available data, the CIR Expert Panel concludes that Peppermint (Mentha Piperita) Oil, Peppermint (Mentha
Piperita) Extract, Peppermint (Mentha Piperita) Leaves, and Peppermint (Mentha Piperita) Water are safe as used in
cosmetic formulations. The concentration of pulegone in these ingredients should not exceed 1%.
Amended Safety Assessment of

Mentha Piperita (Peppermint)-derived Ingredients as Used in
Cosmetics
Status: Re-review for Panel Review

Release Date: March 17, 2017
Panel Date: April 10-11, 2017
The 2017 Cosmetic Ingredient Review Expert Panel members are: Chair, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V.
Belsito, M.D.; Ronald A. Hill, Ph.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; James G. Marks, Jr., M.D.; Ronald
C. Shank, Ph.D.; Thomas J. Slaga, Ph.D.; and Paul W. Snyder, D.V.M., Ph.D. The CIR Director is Lillian J. Gill, D.P.A.
This report was prepared by Wilbur Johnson, Jr., M.S., Senior Scientific Analyst., Bart Heldreth, Ph.D., Chemist, and Ivan
Boyer, Ph.D., Toxicologist.
© Cosmetic Ingredient Review

1620 L STREET, NW, SUITE 1200 ◊ WASHINGTON, DC 20036-4702 ◊ PH 202.331.0651 ◊ FAX 202.331.0088 ◊ CIRINFO@CIR-SAFETY.ORG
INTRODUCTION
The safety of the following ingredients in cosmetics has been reviewed by the Cosmetic Ingredient Review (CIR)
Expert Panel (Panel), and a final report with a conclusion stating that these ingredients are safe as used in cosmetic
formulations was published in 2001: Mentha Piperita (Peppermint) Oil, Mentha Piperita (Peppermint) Leaf Extract, Mentha
Piperita (Peppermint) Leaf, and Mentha Piperita (Peppermint) Leaf Water.1 The conclusion also contains a statement
indicating that the concentration of pulegone in these ingredients should not exceed 1%. According to the International
Cosmetic Ingredient Dictionary and Handbook, these ingredients function mostly as fragrance ingredients and skin
conditioning agents in cosmetic products.2
Most of the safety test data in the 2001 report are on Mentha Piperita (Peppermint) Oil, and the Panel noted that
data on this ingredient are considered relevant to the entire group. The current safety assessment is a re-review of the 4
Mentha Piperita (Peppermint)-derived ingredients, and is inclusive of safety test data that have become available since the
final report was issued. Safety test data and the discussion from the published final report are italicized in the report text.
Some safety test data on menthol, menthone, and pulegone are also included in the published final report and in the re-review
document because these chemicals are components of Mentha Piperita (Peppermint) Oil. Considering that a limitation on
pulegone is mentioned in the original conclusion, it should be noted that a National Toxicology Program (NTP)
carcinogenicity study with positive results on pulegone was published in 2011 and is summarized in the report text.3
The ingredient names, according to the Dictionary, are written as listed above, without italics and unabbreviated.
When referring to the plant from which these ingredients are derived, the standard scientific practice of using italics will be
followed (e.g., Mentha piperita).
In addition to the 4 ingredients that are the subject of this re-review, it should be noted that monographs on the
following additional 6 Mentha piperita-derived ingredients are included in the International Cosmetic Ingredient Dictionary
and Handbook (Dictionary): Mentha Piperita (Peppermint) Extract, Mentha Piperita (Peppermint) Flower/Leaf/Stem
Extract, Mentha Piperita (Peppermint) Flower/Leaf/Stem Water, Mentha Piperita (Peppermint) Leaf Cell Extract, Mentha
Piperita (Peppermint) Leaf Juice, and Mentha Piperita (Peppermint) Meristem Cell Culture. Ingredient literature searches to
identify safety test data have not been performed. These ingredients, along with the Dictionary definitions and functions, are
included in Table 1 (in bold print) of the re-review document. The Panel is being asked to determine whether the Panel’s
safety assessment of Mentha Piperita (Peppermint)-derived ingredients should be expanded to include the additional 6
ingredients.
CHEMISTRY
Definition and General Characterization
The definitions of Mentha Piperita (Peppermint)-derived ingredients are stated in Table 1.2
Chemical and Physical Properties
Properties/specifications relating to Mentha Piperita (Peppermint) Oil are presented in Table 2.1
Method of Manufacture
European and American Peppermint Oil is distilled with steam from the fresh, above-ground parts of the flowering
plant Mentha piperita Linne, rectified by distillation and not dementholized. It has been reported that the menthone content
decreases while the menthol content increases in peppermint leaves upon storage for 1 to 2 months, at 22˚C to 24˚C.
However, the relative menthone to menthol proportion remained practically constant during the total storage time.1
Composition
Pulegone is found in young peppermint leaves, and is metabolized to menthol as the leaves mature. It has also been
reported that pulegone is found only in Mentha Piperita (Peppermint Oil) from young plants and in trace amounts in
“inferior” oils; pulegone is absent from “good quality” Mentha Piperita (Peppermint) Oil. However, a supplier of cosmetic
grade Mentha Piperita (Peppermint) Oil reported Pulegone concentrations of 1% to 4%, depending on the origin of the oil.
Published studies that have investigated the pulegone content of Mentha Piperita (Peppermint) Oil also reported a range of
<1% to 4% for Mentha Piperita (Peppermint) Oils of a North American origin.1
Mentha Piperita (Peppermint) Oil
The major constituents of Mentha Piperita (Peppermint) Oil include: the terpenes (-)-menthol (30-55%), (-)-
menthone (14-32%), (+)-isomenthone (1.5-10%), (-)-menthyl acetate (2.8-10%), (+)-menthofuran (1.0–9.0%), and 1,8-cineol
(3.5-14%).4
Oil was extracted from the leaves of Mentha Piperita harvested (first in July and second harvest in September) in
Washington state.5 Certain trends were observed between oil extracted from first and second harvest leaves, and oil extracted
from fresh leaves versus dried leaves. When compared to the second harvest, oils from the first harvest were generally
higher in (Z)-3-hexenol, 1,8-cineole, α-pinene, β-pinene, sabinene hydrate, isomenthone, menthofuran, pulegone, β-
caryophyllene, and germacrene d, but lower in limonene, menthol, and menthone. When compared to oils from dried leaves,
oils from fresh leaves were higher in 1,8-cineole, α-pinene, limonene, isomenthone, menthofuran, menthone, pulegone and
lower in β-caryophyllene, germacrene d, and menthol. Menthyl formate was found in all of the Mentha Piperita (Peppermint)
Oils (from leaf extraction) that were analyzed.
Regarding the essential oil composition of Mentha piperita adult plants (in Poland), menthone, menthol,
menthyl acetate, carvone, piperitone, 1,8-cineole, and pulegone have been identified as major components.6
According to the United States Pharmacopeial Convention’s (USP) Food Ingredients Expert Committee, the
acceptance criteria for Mentha Piperita (Peppermint) Oil include not less than 5% total esters (calculated as menthyl acetate)
and not less than 50% menthol.7
Mentha Piperita (Peppermint) Leaf Extract
An analysis of Mentha Piperita (Peppermint) Leaf indicated that the leaves principally contained the cinnamic acid
caffeic acid, the depside rosmarinic acid, and flavonoids (flavones and flavanones).8 Eriocitrin (383.3 ± 2.2 mg/g extract)
and rosmarinic acid (381.2 ± 1.9 mg/g extract) were the most abundant components identified within the leaves, while
naringenin-7-O-glucoside (0.8 ± 0.01 mg/g extract) was the least abundant component identified.
Kynurenic acid (3.82 ± 0.46 µg/g) has also been detected in Mentha Piperita (Peppermint) Leaf Extract.9 It should
be noted that kynurenic acid is a constituent of human synovial fluid.
Mentha Piperita (Peppermint) Leaf
The major monoterpene constituents of Mentha Piperita (Peppermint) Leaf are as follows: (-)-limonene; 1,8-
cineole; (+)-pulegone; (-)-menthone; (+)-isomenthone; (+)-menthofuran; (-)-menthol; and (+)-neomenthol.10 It has been
reported that Mentha Piperita (Peppermint) Leaf contains a toxic compound, pennyroyal (concentration not stated), which can
damage the liver.11
Impurities
Mentha Piperita (Peppermint) Leaf
The following microelements have been detected in Mentha piperita herbal tea samples (n = 3) from Serbia:
manganese (111.97 mg/kg dry weight), iron (443.90 mg/kg), copper (17.15 mg/kg), and zinc (26.86 mg/kg), molybdenum
(2.695 mg/kg), cobalt (0.161 mg/kg), nickel (1.882 mg/kg), selenium (0.107 mg/kg), aluminum (554 mg/kg), and tin (3.66
mg/kg).12
In a study in which Mentha Piperita (Peppermint) Leaves were soaked in pesticides, the dissipation rate of pesticide
residues during the drying process was said to have been satisfactory, except for the pirimiphos-ethyl pesticide, because of its
high octanol-water partition coefficient and low vapor pressure.13
USE
Cosmetic
The safety of Mentha Piperita (Peppermint)-derived ingredients is evaluated based on data received from the U.S.
Food and Drug Administration (FDA) and the cosmetics industry on the expected use of this ingredient in cosmetics. Use
frequencies of individual ingredients in cosmetics are collected from manufacturers and reported by cosmetic product
category in FDA’s Voluntary Cosmetic Registration Program (VCRP) database.14 Use concentration data are submitted by
the cosmetics industry in response to surveys, conducted by the Personal Care Products Council (Council), of maximum
reported use concentrations by product category.15
According to 2017 VCRP data, the greatest use frequency is being reported for Mentha Piperita (Peppermint) Oil,
which is being used in 827 cosmetic products (433 leave-on products + 360 rinse-off products + 34 products diluted for bath
use).14 The results of a concentration of use survey conducted in 2016 indicate that Mentha Piperita (Peppermint) Leaf Water
is being used at concentrations up to 15% in leave-on products, which is the greatest use concentration that is being reported
for Mentha Piperita (Peppermint)-derived ingredients reviewed in this safety assessment.15 Current and historical use
frequency and concentration of use data are presented in Table 3.
Cosmetic products containing Mentha Piperita (Peppermint)-derived ingredients may be applied to the skin and hair
or, incidentally, may come in contact with the eyes (at maximum use concentrations up to 0.0018 % [Mentha Piperita
(Peppermint) Leaf Extract] in eye lotions) and mucous membranes (at maximum use concentrations up to 3.9% [Mentha
Piperita (Peppermint) Oil] in bath oils, tablets, and salts). Additionally, use in lipstick products (at maximum use
concentrations up to 2.9% [Mentha Piperita (Peppermint) Oil]) is being reported, the application of which may result in
incidental ingestion. Products containing Mentha Piperita (Peppermint)-derived ingredients may be applied as frequently as
several times per day and may come in contact with the skin or hair for variable periods following application. Daily or
occasional use may extend over many years.
Mentha Piperita (Peppermint) Oil is being used in both pump hair sprays (maximum use concentrations up to
0.02%) and aerosol hair sprays (maximum use concentrations up to 0.017%) which may result in incidental inhalation
exposure. Additionally, use of this ingredient in foot sprays at maximum use concentrations up to 0.5% is being reported.
Mentha Piperita (Peppermint) Leaf Extract is also being used in pump and aerosol hair sprays, but at lower maximum use
concentrations, and in face and neck/body and hand spray products at maximum use concentrations up to 0.001%. In
practice, 95% to 99% of the droplets/particles released from cosmetic sprays have aerodynamic equivalent diameters >10 µm,
with propellant sprays yielding a greater fraction of droplets/particles below 10 µm, compared with pump sprays.16,17,18,19
Therefore, most droplets/particles incidentally inhaled from cosmetic sprays would be deposited in the nasopharyngeal and
bronchial regions and would not be respirable (i.e., they would not enter the lungs) to any appreciable amount.16,17
Mentha Piperita (Peppermint) Oil is being used in foot powders at maximum use concentrations up to 1%, and
Mentha Piperita (Peppermint) Leaf Extract is being used in face powders at maximum use concentrations up to 0.0018%.
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 the
workplace.20,21,22
Noncosmetic
Mentha Piperita (Peppermint) Oil is a generally recognized as safe (GRAS) ingredient for use in dietary
supplements. It is described as a naturally occurring carminative that relaxes gastrointestinal smooth muscle. A final ruling
by the FDA labeled Mentha Piperita (Peppermint) Oil as safe and effective as an antitussive (topical/inhalant). Final rulings
cautioned that Mentha Piperita (Peppermint) Oil is not safe and effective for use as an expectorant in either topical/inhalant
or lozenge form, or for use as a nasal decongestant, mouthwash, or digestive aid.1
Mentha Piperita (Peppermint) Oil is generally recognized as safe for use in food for human consumption.23 It is also
an inactive ingredient in drug products that have been approved by the United States Food and Drug Adminsitration (FDA).24
A number of active ingredients, Mentha Piperita (Peppermint) Oil included, have been present in over-the-counter (OTC)
drug products for various uses.25 However, the FDA has determined that, based on evidence currently available, there are
inadequate data to establish general recognition of the safety and effectiveness of Mentha Piperita (Peppermint) Oil as an
active ingredient in the following drug products: nasal decongestant drug products, digestive aid drug products, insect bite
and sting drug products, and astringent drug products.
Mentha Piperita (Peppermint) Oil is on the United States Environmental Protection Agency’s list of active
ingredients eligible for minimum risk pesticide products.26
Mentha Piperita
According to the European Medicines Agency Committee on Herbal Medicinal Products (HMPC) community
herbal monograph on Mentha x piperita L., aetheroleum, this herbal medicine is administered orally for the symptomatic
relief of minor spasms of the gastrointestinal tract, flatulence, and abdominal pain, especially in patients with irritable
bowel syndrome.27 It is also an herbal medicine that is administered cutaneously for the symptomatic relief of mild tension-
type headache. These uses have been identified as well-established uses by the HMPC.
TOXICOKINETIC STUDIES
Dermal Penetration
Animal
Eserine in a Mentha Piperita (Peppermint) Oil vehicle was applied to a 2.2 cm2 shaved area on the abdomen of
mice. The absorption rate for Mentha Piperita (Peppermint) Oil was measured as the latent period between application and
appearance of serine-induced signs. Mentha Piperita (Peppermint) Oil had a latent period of 58 minutes.1
Dermal
Penetration Enhancement
The skin penetration enahancement potential of Mentha piperita leaf extract (aqueous ethanol extract) was evaluated
using dorsal porcine skin (dermatomed to thickness of 500 µm).28 A square section of skin was cut to provide a dose area of 1
cm2 and placed in a flow-through diffusion cell. 14C-caffeine (hydrophilic) or 14C-salicylic acid (hydrophobic) was applied
topically with 10% Mentha Piperita (Peppermint) Leaf Extract to porcine skin. Ethanol alone served as the control. When
compared to 14C-caffeine in the presence of ethanol (control), the dermal absorption of 14C-caffeine was significantly greater
(p > 0.05; fllux and permeability of caffeine increased by over 3-fold) in the presence of Mentha Piperita (Peppermint) Leaf
Extract. However, this was not true for 14C-salicylic acid.
Penetration Inhibition
Mentha Piperita (Peppermint) Oil and [ring-UL-14C]benzoic acid were applied to full-thickness human skin (breast
or abdominal) samples in a static diffusion cell.29 As the concentration of Mentha Piperita (Peppermint) Oil increased from
zero to 5% in the donor phase, the maximal flux of benzoic acid decreased. The differences were significant at 1.0% and
5.0% Peppermint Oil, where the maximal fluxes were reduced to 81% and 52% of the control, respectively.
Absorption, Distribution, Metabolism, and Excretion
Human
Oral
The rate of Mentha Piperita (Peppermint) Oil absorption and excretion following oral administration was
determined by measuring urinary menthol glucuronide. Four male volunteers ingested 180 mg of an enteric-coated Mentha
Piperita (Peppermint) Oil-coated capsule following a 16-h fast. Menthol was liberated from its glucuronide metabolite by
treating the urine with β-D-glucuronidase. It was estimated that between 37 and 116 mg of menthol corresponding to an
average 40% recovery of the administered menthol dose was excreted by each panelist within 14 h.1
Mentha Piperita (Peppermint) Oil is relatively rapidly absorbed after oral administration and eliminated mainly via
the bile.4 The major biliary metabolite is menthol glucuronide, which undergoes enterohepatic circulation. The urinary
metabolites result from hydroxylation at the C-7 methyl group at C-8 and C-9 of the isopropyl moiety, forming a series of
mono- and dihydroxymenthols and carboxylic acids, some of which are excreted, in part, as glucuronic acid conjugates.
Studies with tritiated I-menthol in rats indicated approximately equal excretion in the feces and urine. The main metabolite
identified was menthol-glucuronide. Additional metabolites are mono- or di-hydroxylated menthol derivatives.
TOXICOLOGICAL STUDIES
Acute Toxicity Studies
Oral
Mentha Piperita (Peppermint) Oil had a 24-h oral LD 50 of 4441 mg/kg in fasted Wistar rats; the 48-h LD 50 was
2426 mg/kg. In a study involving fasted mice, an LD 50 of 2410 mg/kg was reported for Mentha Piperita (Peppermint) Oil
diluted in olive oil.1
Short-Term Toxicity Studies
Oral
Mentha Piperita (Peppermint) Oil and Components
In 3 of 4 short-term oral toxicity studies (28-day or 5-week studies) involving 20 to 28 rats per group, brain lesions
(specifically, cyst-like spaces in the cerebellum) were observed at Mentha Piperita (Peppermint) Oil doses up to 100
mg/kg/day. In the remaining study (12 rats per group), these lesions were not observed in rats dosed with Mentha Piperita
(Peppermint) Oil at doses of 20, 150, or 500 mg/kg/day for 5 weeks. In short-term oral toxicity studies (28-day studies; 20
rats per group) on components of Mentha Piperita (Peppermint) Oil, brain lesions (specifically, cyst-like spaces in the
cerebellum) were also observed in rats given pulegone doses up to 160 mg/kg/day and menthone doses up to 800 mg/kg/day.
These lesions were not observed in groups of 20 rats given oral doses of menthol up to 800 mg/kg/day for 28 days.1
Mentha Piperita (Peppermint) Leaf (as Mentha Piperita Tea)
The effects of Mentha piperita tea on rat kidney tissue were evaluated. The tea (prepared daily) was made by
pouring 250 ml of boiling water over one heaped teaspoon (5 g) of the dried leaves of Mentha piperita L (grown in Turkiey)
and steeping for 5 to 10 minutes. Groups of 12 male Wistar albino rats were used: Test animals received Mentha piperita tea
(20 g/l) in drinking water for 30 days. Control rats were given commercial drinking water during the study. The following
histopathological changes, described as slight, were reported for the group dosed with mentha piperita tea: hydropic
degeneration of tubular epithelial cells, epithelial cells with pyknotic nuclei and eosinophilic cytoplasm, tubular dilatation
and enlargements in Bowman capsules. In conclusion, the results indicate that Mentha. piperita does not show
nephrotoxicity.30
Subchronic Toxicity Studies
Oral
Groups of 28 Wistar rats were given oral doses of 10, 40, and 100 mg/kg Mentha Piperita (Peppermint) Oil (diluted
with soybean oil) daily for 90 days. All hematological and biochemical parameters were within normal range, and there were
no significant differences in absolute and relative organ weights. Brain lesions (specifically, cyst-like spaces in the
cerebellum) were observed in all dose groups, but these results were classified as significant only for animals of the 100
mg/kg/day dose group. No other lesions of encephalopathy were observed. Nephropathy (hyaline droplet formation) was
observed only in male rats of the 100 mg/kg/day dose group, and there was no evidence of epithelial degeneration. The no-
observed-adverse-effect level (NOAEL) for Mentha Piperita (Peppermint) Oil was 40 mg/kg/day in this study.1
Chronic Toxicity Studies
Dermal
Exposure Assessment
The FDA calculated an estimated human exposure from cosmetic use based on the concentration of use information
supplied by industry. Using a body splash product containing 0.2% Mentha Piperita (Peppermint Oil) and assuming 100%
absorption over a body surface of 17,000 cm2 and a daily application of 1 mg/cm2 (~17 ml of the product), the FDA estimated
an exposure of 34 mg/day. For a 60-kg person, this amounted to an estimated daily dose of 0.6 mg/kg/day.1
Oral
Human
Mentha Piperita
A study was performed to characterize data on dietary botanical supplement (DBSs) associated with adverse event
reports submitted to the FDA Center for Food Safety and Applied Nutrition’s Adverse Event Reporting System (CAERS).31
FDA obtained CAERS data from 1999 to 2003 involving adverse effects associated with the 6 most frequently used DBSs,
including peppermint. No adverse events were reported for single-ingredient peppermint supplements during the study
period.
DEVELOPMENTAL AND REPRODUCTIVE TOXICITY STUDIES
Oral
Animal
Menthol
Groups of 15 to 23 pregnant animals were dosed by oral intubation with natural Brazilian menthol. The mice were
dosed with up to 185 mg/kg/day on gestation days (GD) 6 to 15; pregnant rats were given doses up to 218 mg/kg on GDs 6 to
15; pregnant hamsters were given doses up to 405 mg/kg/day on GDs 6 to 10; and artificially inseminated rabbits were given
doses up to 425 mg/kg/day on GDs 6 to 18. Maternal body weight was recorded regularly. Caesarean sections were
performed on all dams. No teratogenic effects were observed.1
GENOTOXICITY STUDIES
In Vitro
Mentha Piperita (Peppermint) Oil and Components
The mutagenic potential of Mentha Piperita (Peppermint) Oil and its components was investigated using the
Salmonella/mammalian microsome test. The following Salmonella strains were used: TA1535, TA100, TA1537, and TA98.
The sample tested contained 38.1% menthol, 33.7% menthone, and 1.7% pulegone; the remaining components were not
identified. Mentha Piperita (Peppermint) Oil, menthol, and pulegone, all tested at doses of 6.4, 32, and 160 µg/plate,
produced the same number of revertants as the negative control. Toxicity was noted at the next (and maximum) dose of 800
µg/plate. Metabolic activation appeared to have made the compounds less toxic to the bacteria. In contrast, menthone,
induced a statistically significant number of revertants in strain TA1537 at doses of 6.4 and 32 µg/plate without metabolic
activation. Menthone was further tested using the more sensitive TA97 strain. Statistically significant increases in the
number of revertants were noted at all doses tested without metabolic activation; the results were dose-related (though
toxicity was observed at a dose of 800 µg/plate). The researchers remarked on the unexpected results – methone was
mutagenic, but Mentha Piperita (Peppermint) Oil, which contained 33.7% menthone, was not.1
In an in vitro chromosomal aberration test using a Chinese hamster fibroblast cell line, Mentha Piperita
(Peppermint) Oil, at a maximum concentration of 0.25 mg/ml (in ethanol), produced polyploidism in 3% of the cells and
structural aberrations in 7% of the cells at 48 h after treatment. The results were considered equivocal, as scores of either ≥
10% or ≤ 4.9% were necessary for classification as either positive or negative, respectively. The results for Mentha Piperita
(Peppermint) Oil (150 µg/ml) were negative in a mouse lymphoma L5178Y TK +/- cell mutagenesis assay. Results were also
negative for this ingredient (at 155 µg) in an unscheduled DNA synthesis assay using rat hepatocytes.1
The genotoxicity of Mentha Piperita (Peppermint) Oil was evaluated in a chromosome aberration test using human
peripheral blood lymphocytes.32 Lymphocyte cultures were incubated for 24 h with test substance concentrations up to 0.30
µl/ml. When chromosome aberrations (chromatid breaks, chromatid exchanges, chromosome breaks, and chromosome
exchanges) were scored, not less than 100 metaphases per culture were analyzed. Mentha Piperita (Peppermint) Oil was the
most clastogenic at a concentration of 0.20 µl/ml (8-fold increase over acetone solvent control); the number of aberrant cells
decreased at higher concentrations. The authors noted that the dose-response curve for Mentha Piperita (Peppermint) Oil was
complicated, with a clear peak response at a concentration of 0.20 µl/ml.
Mentha Piperita (Peppermint) Oil was tested at concentrations up to 0.30 µl/ml in the sister chromatid exchange
(SCE) test involving human lymphocytes.32 The test conditions were essentially the same as those in the preceding
chromosome aberration test, with the exception that 5-bromo-2'-deoxyuridine was added (10 µg/ml) to cultures initially. To
determine the replicative index, 200 cells were scored. Mentha Piperita (Peppermint) Oil induced sister chromatid exchanges
in a dose-independent manner. The authors noted that, seemingly, the saturation of SCE-inducing capacity occurred at high
concentrations of Mentha Piperita (Peppermint) Oil. Results also indicated that Mentha Piperita (Peppermint) Oil inhibited
cell replicative kinetics, some signs of which were observed at a concentration of 0.15 µl/ml. At concentrations ≥ 0.20 µl/ml,
statistically significant inhibition of cell replicative kinetics was evident.
Menthol
The mutagenic potential of natural Brazilian menthol was tested in the cytogenetic assay (rats), the host-mediated
assay (mice), and the dominant lethal assay (rats). The assays were performed with menthol doses of 1.45, 14.5, and 145
mg/kg, and, in some instances, subacute and acute studies were performed with doses of 500, 1150, and 3000 mg/kg, or 5000
mg/kg. In the host-mediated assay, a weakly positive but significant response was noted with the acute high dose against
Salmonella typhimurium TA1530, and elevated recombinant frequencies were noted with the subacute doses against
Saccharomyces strain D3. All of the other assay results were negative.1
ANTIGENOTOXICITY STUDIES
Oral pretreatment with Mentha Piperita (Peppermint) Leaf Extract (aqueous extract) (1 g/kg/day for 3 consecutive
days) before exposure to gamma radiation was found to be effective in protecting against chromosomal damage in the bone
marrow of Swiss albino mice (number tested not stated).33 The exposure of mice to 8 Gy gamma radiation only resulted in
chromosomal aberrations in the form of chromatid breaks, chromosome breaks, centric rings, dicentrics, exchanges, and
acentric fragments. In mice pretreated with Mentha Piperita (Peppermint) Leaf Extract, there was a significant decrease in
the frequency of aberrant cells when compared to the irradiated control. A significant increase in the percentage of chromatid
breaks, chromosome breaks, centric rings, dicentrics, exchanges, acentric fragments, total aberrations, and
aberrations/damaged cell was observed at 12 h post-irradiation necropsy time in control animals. However, a significant
decrease in the percentage of aberrations of this type was observed in mice pretreated with Mentha Piperita (Peppermint)
Leaf Extract.
The modulatory effects of Mentha Piperita (Peppermint) Leaf Extract (aqueous extract) on genotoxicity and lung
tumor incidence were evaluated using 4 groups of 30 to 76 Swiss albino mice.34 Beginning at 3 weeks of age (weaning), the
mice received a single subcutaneous injection of benzo(a)pyrene and were then dosed orally (by gavage) with either water
(group of 53 mice) or Mentha Piperita (Peppermint) Leaf Extract (1 g/kg; group of 76 mice). The remaining 2 groups of
mice in the study were identified as no benzo(a)pyrene or Mentha Piperita (Peppermint) Leaf Extract dosing (30 mice) and
Mentha Piperita (Peppermint) Leaf Extract alone (30 mice). When compared to mice in the benzo(a)pyrene only group,
Mentha Piperita (Peppermint) Leaf Extract reduced the frequency of chromosomal aberrations and micronuclei in bone
marrow cells. Mentha Piperita (Peppermint) Leaf extract had an antigenotoxic effect in this study. Results relating to the
modulatory effect of Menta Piperita (Peppermint) Leaf Extract on lung tumor formation are included in the
Anticarcinogenicity section of the report text.
CARCINOGENICITY STUDIES
Oral
In a carcinogenicity study of toothpaste and its components, groups of 52 male pathogen-free CFLP (ICI-redefined)
mice were dosed by gavage with 4 or 16 mg Mentha Piperita (Peppermint) Oil/kg/day, 6 days per week for 80 weeks.
Treatment was followed by a 16- to 24-week observation period. An untreated group of 52 male mice and a vehicle control
group of 260 male mice that received the toothpaste base (which did not contain chloroform, eucalyptol, or Mentha Piperita
(Peppermint) Oil) were maintained as controls. At least one neoplasm at any site was observed in 73%, 69%, 65%, and 71%
of mice of the low-dose, high-dose, untreated control, and vehicle control groups, respectively. The incidence of neoplasms
of the lungs and kidneys was comparable among mice of the treated and nontreated groups. Hepatic cell tumor incidence for
Mentha Piperita (Peppermint) Oil-dosed mice (25%) was comparable to the incidence for mice of the vehicle control group
(27%); the incidence for the untreated group was 19%. Malignant lymphoma was found in 25%, 21%, 10%, and 14% of
mice of the low-dose, high-dose, untreated, and vehicle control groups, respectively. The researchers did not discuss
whether the differences in tumor incidence were significant.1
Menthol
A 2-year oral dosing study by the National Cancer Institute found no evidence of carcinogenicity after Fischer 344
rats were dosed with 3750 ppm or 7500 ppm d,l-menthol or after B6C3F 1 mice were dosed with 2000 ppm or 4000 ppm d,l-
menthol. A negative trend in fibroadenomas of the mammary gland was observed in female rats (20 of 50 control; 10 of 49
low-dose; 7 of 49 high-dose).1
Pulegone
In a 2-year bioassay, the administration of pulegone to groups of 50 male and 50 female F344/N rats and groups of
50 male and 50 female B6C3F1 mice by corn oil gavage (5 days/week) showed high morbidity and mortality at high doses in
rats and decreased body weight gains in rats and mice.3,35 Effects in the kidneys (hyaline glomerulopathy and nephropathy),
liver (oval cell hyperplasia, bile duct hyperplasia, hypertrophy, hepatocyte necrosis, and portal fibrosis), nose (olfactory
epithelium degeneration, inflammation, and metaplasia), and forestomach (inflammation, hyperplasia, and ulcer) were
reported. Increased incidences of liver neoplasms in male and female B6C3F1 mice in the study led to the conclusion that
there was clear evidence of carcinogenic activity in mice. For female F344/N rats, it was concluded that there was some
evidence of carcinogenicity based on an increased incidence of urinary bladder neoplasms. Five of 47 rats in the 150 mg/kg
female stop-exposure group (gavage with pulegone stopped at week 60 because of severely reduced body weights) were
diagnosed with papilloma and carcinoma, combined. Male rats did not show increased incidences of bladder tumors or
neoplasms of other organs.
A subsequent study supporting the hypothesis that cytotoxicity followed by regenerative cell proliferation is the
mode-of-action for pulegone-induced urothelial tumors in female rats has been performed.35
ANTICARCINOGENICITY STUDIES
The modulatory effects of Mentha Piperita (Peppermint) Leaf Extract (aqueous extract) on genotoxicity and lung
tumor incidence were evaluated using 4 groups of 30 to 76 Swiss albino mice.34 Beginning at 3 weeks of age (weaning), the
mice received a single subcutaneous injection of benzo(a)pyrene and were then dosed orally (by gavage) with either water
(group of 53 mice) or Mentha Piperita (Peppermint) Leaf Extract (1 g/kg; group of 76 mice). The remaining 2 groups of
mice in the study were identified as no benzo(a)pyrene or Mentha Piperita (Peppermint) Leaf Extract dosing (30 mice) and
Mentha Piperita (Peppermint) Leaf Extract alone (30 mice). The mice were killed at 9 weeks of age and evaluated for lung
tumor incidence. Dosing with Mentha Piperita (Peppermint) Leaf Extract caused a significant reduction in the number of
lung adenomas from an incidence of 67.92% in mice given benzo(a)pyrene only to 26.31%, which amounted to 61.26%
inhibition. Tumor multiplicity was 1.22 in the benzo(a)pyrene only group and 1.15 in the benzo(a)pyrene + Mentha Piperita
(Peppermint) Leaf Extract group. Mentha Piperita (Peppermint) Leaf Extract had an inhibitory effect on lung tumor
formation in this study. Results relating to the modulation of genotoxicity are included in the Antigenotoxicity section of the
report text.
The anticancer potential of Mentha Piperita (Peppermint) Leaf Extract was studied using Swiss albino mice (number
not stated).36 Two stage mouse skin carcinogenesis was initiated by 7,12-dimethyl benz(a)anthracene (DMBA). Two weeks
later, croton oil (promoter) was applied 3 times per week for 14 weeks. The mice were dosed orally with Mentha Piperita
(Peppermint) Leaf Extract (800 mg/kg/day) for the same period. At the end of the dosing period, average latent period,
tumor incidence, size, burden, weight and cumulative number of papillomas were assessed. Dosing with Mentha Piperita
(Peppermint) Leaf Extract caused inhibition of skin papilloma formation induced by DMBA and the application of croton oil,
in terms of a significant decrease in the cumulative number of papillomas, tumor burden, and tumor incidence. In the control
group, the tumor incidence was 100 percent. However, after dosing with the test substance for 15 days, the tumor incidence
was reduced to 64%. There was a significant increase in the latency period for the appearance of papillomas in test animals
(11 weeks in control group; 13 weeks in test group).
The possible molecular mechanisms underlying the cytotoxicity and anticarcinogenic potential of Mentha Piperita
(Peppermint) Leaf Extract (petroleum ether, benzene, chloroform, ethyl acetate, methanol, or water extract) on 6 human
cancer (HeLa, MCF-7, Jurkat, T24, HT-29, MIAPaCa-2) and normal (IMR-90, HEK-293) cell lines were evaluated.37 In the
human cancer cell lines tested with doses of 1 µg/ml, 10 µg/ml, and 100 µg/ml for 6 h, the number of apoptotic
cells was incremental with an increase in the dose of Mentha piperita extracts. However, of all the extracts tested, the
chloroform and ethyl acetate extracts resulted in a significantly higher apoptotic index after 6 hours, and the results were
dose-dependent. When compared to the cancer cell lines, no significant changes were observed in normal cells. Similarly, of
all of the extracts tested, chloroform and ethyl acetate extracts of Mentha piperita had significant dose- and time-dependent
anticarcinogenic activity, leading to G1 cell cycle arrest and mitochondrial-mediated apoptosis, perturbation of oxidative
balance, upregulation of Bax gene, elevated expression of p53 and p21 in the treated cells, and acquisition of senescence
phenotype, while inducing pro-inflammatory cytokines response.
A study was performed to evaluate the antitumor activity of Mentha Piperita (Peppermint) Leaf Extract (methanol
extract), using SW-480 human colon adenocarcinoma cells in a relevant cell anti-proliferation assay.38 Statistically
significant (α = 0.05) growth inhibition was observed at a concentration of 31µg/ml. An IC 50 (concentration required for
50% inhibition, µg/ml) of 92.3µg/ml was reported for Mentha Piperita (Peppermint) Leaf Extract.
Menthol
Significant inhibition (p < 0.001) of 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary gland

carcinogenesis following 20 weeks of oral dosing with 1% (-)-menthol. Dosing with menthol began 2 weeks prior to DMBA
tumor induction. A chemopreventive effect was noted when rats were dosed with 0.5% menthol for 2 weeks prior to and 1
week after DMBA induction. 1
OTHER RELEVANT STUDIES
Cytotoxicity
The cytotoxicity of Mentha Piperita (Peppermint) Oil was evaluated in the (3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyltetrazolium bromide (MTT) assay using 2 human cancer cell lines, MCF-7 and LNCaP.39 Mentha Piperita
(Peppermint) Oil from plants that were harvested during the summer and winter was tested. The following IC 50 values were
reported: MCF-7 cell line (75.2 ± 2.9 [summer]; 80.8 ± 3.2 [winter]) and LNCaP cell line (90.4 ± 3.7 [summer]; 95.7 ± 4.5
[winter]). IC 50 values in the 10 to 100 µg/ml range represented a potentially toxic chemical, and IC 50 values < 10µg/ml
represented a potentially very toxic chemical.
In another study, essential oil was extracted from the leaves of Mentha piperita.40 This extract was found to be
cytotoxic in the following following 4 human cancer cell lines: human lung carcinoma SPC-A1 cells (IC 50 = 10.89 µg/ml),
human leukemia K562 cells (IC 50 = 16.16 µg/ml) and human gastric cancer SGC-7901 cells (IC 50 = 38.76 µg/ml). The
extract was inactive against human hepatocellular carcinoma BEL-7402 cells.
Mentha Piperita
The inhibitory effect of Mentha piperita on A549 non-small cell lung adenocarcinoma cells was investigated using
the MTT assay.41 The results indicated that Mentha piperita had a moderate toxic effect on the A549 cell line (IC 50 = 879.52
± 22.55 μg/ml). The growth of A549 cells was inhibited by Mentha piperita in a dose-dependent manner. The inhibitory rate
was 54.54% ± 1.38% at the highest concentration tested (1 mg/ml).
Hepatotoxicity
Mentha Piperita (Peppermint) Leaf Extract (methanol extract) and other botanical extracts were tested on both
human (HepG2/C3A) and rat (MH1C1) hepatoma cells, using a battery of toxicity endpoints.42 The following 8 endpoints
covering a variety of biological activities relevant to hepatotoxicity were used for hepatotoxicity evaluation: oxidative stress,
mitochondrial membrane permeability, cellular neutral and polar lipid accumulation, CYP1A, 2B, 3A activities, albumin
excretion, and total DNA content. Cluster analysis was used to group the phenolics into 4 clusters for each cell type. Two of
the clusters were cluster 1 (compounds clustering with the solvent control [dimethyl sulfoxide [DMSO]) and cluster 2
(compounds with reported in vivo liver toxicity). Overall and individual liver activity of the phenolics on both human and rat
hepatoma cell lines were compared. For HepG2/C3A cells, 100% of the observations for Mentha Piperita (Peppermint) Leaf
Extract and thyme extract, 92% for cinnamon extract, and 89% for juniper berry extract were assigned to cluster 1 (control
group). For rat MH1C1 cells, 100% of the juniper berry extract and Mentha Piperita (Peppermint) Leaf Extract observations
were assigned to cluster 1. The authors noted that because there are currently no reports of liver toxicity associated with
peppermint, Mentha Piperita (Peppermint) Leaf Extract is useful as a negative control.
Effect on Histamine Release
The 50% ethanol extract of peppermint leaves and stems significantly inhibited histamine release from rat peritoneal
mast cells that was induced by compound 48/80 (polymer produced by the condensation of N-methyl-p-
methoxyphenethylamine with formaldehyde) in vitro.43
Mentha Piperita
In a study involving human basophil cell suspensions, obtained from workers who were exposed to an additive
containing penicillin, the cell suspensions were incubated with 10-1 to 10-3 mg/ml Peppermint (dry aroma). A dose-dependent
increase in histamine release was noted, and it was concluded that this release was due to nonimmunological mechanisms.1
Immune System Effects
The results of a host-resistance assay involving groups of 20 mice that had been dosed orally with Mentha Piperita
(Peppermint) Oil (up to 1250 mg/kg/day for 5 days) suggested immunosuppression and/or increased susceptibility to
bacterial-induced mortality. The results of a plaque-forming assay involving groups of 10 mice that received the same oral
doses were negative.1
Effect on Hair Growth
In a study involving C57BL/6 mice, the data suggest that 3% Mentha Piperita (Peppermint) Oil (diluted in jojoba
oil) facilitates hair growth by promoting the conservation of vascularization of hair dermal papilla, which may contribute to
the induction of early anagen stage.44
DERMAL IRRITATION AND SENSITZATION STUDIES
Irritation
Animal
Hairless sites on 5 white rabbits were injected intradermally with 0.05 ml Mentha Piperita (Peppermint) Oil. Gross
examinations were performed at 24 h and 48 h, at 1 and 2 weeks, and, in some cases, at 1 month after dosing. Dosing was
repeated between 5 and 10 times. At microscopic examination of skin samples, moderate reactions characterized by
polymorphonuclear leucocytes, lymphocytes, and plasma cells (without necrosis) were observed in 3 rabbits. Severe
reactions, which were marked by the above as well as necrosis, were observed in the other 2 rabbits.1
Menthol
Two Tiger Balm formulations containing 8% and 10% menthol were applied for 23 h under occlusive patches to
abraded and intact sites on New Zealand white rabbits. The total number of patches applied was 21. A third group was
treated with a control wax (mixture of hard and soft waxes). Untreated sites on each animal served as negative controls.
Irritation was scored using the Draize scale. Dermal irritation was observed in all treated animals with the following
severity scale: 8% menthol balm < control wax < 10% menthol balm. The 8% menthol balm was almost innocuous in male
rabbits. The irritation observed was not progressive and tolerance developed within 10 days. No severe damage was noted
at microscopic examination of the skin (increased hyperkeratosis was noted at treated sites) and no evidence of systemic
toxicity was noted. The investigators noted that the balm contained “irritants” such as clove oil, camphor, and menthol and
remarked that the irritation observed was unexpected.1
Human
Mentha Piperita (Peppermint) Leaf Water
Mild to moderate erythema was observed in human skin irritation studies on a product containing Mentha Piperita
(Peppermint) Leaf Water and the diluted product. Skin irritation data are summarized in Table 4.45,46
Sensitization
Human
In the maximization test, 25 healthy male panelists received five 48-h occlusive induction patch (containing 8%
Mentha Piperita (Peppermint) Oil) applications. Pre-treatment was for 24 h with an occlusive patch containing 5% sodium
lauryl sulfate (SLS) prior to each exposure. After a 10-day non-treatment period, the subjects were challenged on the back
with a 48-h patch (also preceded by SLS treatment). No evidence of sensitization was found.1

and Mentha Piperita (Peppermint) Leaf Water
Negative skin irritation and sensitization data on a product containing Mentha Piperita (Peppermint) Leaf Water are
summarized in Table 4.47
Photosensitization/Phototoxicity
Animal
Undiluted Mentha Piperita (Peppermint) Oil was applied to the backs of 6 Skh:hairless mice. Thirty minutes later,
the mice were irradiated for either 1 h with light from a fluorescent blacklight at an integrated UVA of 3 W/m2, or for 40
minutes with light from a Xenon lamp at a weighted erythema energy of 0.1667 W/m2. The mice were examined at 4 h, 24 h,
48 h, 72 h, and 96 h after radiation treatment. No effects were noted. In a second experiment, using 2 miniature swine and
following the same protocol, no effect was produced by 100% Mentha Piperita (Peppermint) Oil.1
OCULAR IRRITATION STUDIES
Human
The ocular irritation potential of a cleansing gel containing 50% Mentha Piperita (Peppermint) Leaf Water was
studied using 50 subjects.45 The subjects applied the product twice per day for 4 weeks, and were instructed to record any
signs felt or observed during product use. Product use did not cause any signs of ocular or palpebral irritation.
CLINICAL STUDIES
Multicenter Studies
Negative skin irritation and sensitization data on Mentha Piperita (Peppermint) Oil (multicenter study) are
summarized in Table 4.48
Case Reports
Mentha Piperita (Peppermint) Oil, Mentha Piperita (Peppermint) Leaf,

Mentha Piperita (Peppermint) Leaf Extract, and Mentha Piperita
Mostly positive patch test reactions to Mentha Piperita (Peppermint) Oil and Mentha Piperita were reported in case
reports on patients with diseased skin.49,50,51,52,53,54,55 Though positive patch test results were reported in one of the studies on
Mentha Piperita (Peppermint) Oil, prick test results in that study were negative. In patients without skin disease, but with
peppermint sensitivity, positive prick test reactions to Mentha Piperita (Peppermint) Leaf, Mentha Piperita (Peppermint) Leaf
Extract, and Mentha Piperita were reported.56,57 Case reports are summarized in Table 4.
Other Clinical Reports
Positive reactions were observed in 7 of 450 dermatitic patients who were patch tested with 2% Mentha Piperita
(Peppermint) Oil in yellow soft paraffin. In another study, positive reactions to 2% Mentha Piperita (Peppermint) Oil were
observed in 6 of 86 dermatitic patients. A patch containing 1% Mentha Piperita (Peppermint) Oil (vehicle unknown) was
applied to the backs of 56 patients with chronic urticaria. No reactions were noted after a 1-h or 48-h exposure.1
No reactions were observed in 25 spice factory workers who were patch tested with 2% Mentha Piperita
(Peppermint) Oil in petrolatum. It has been reported that the patch testing of individual components of Mentha Piperita
(Peppermint) Oil using 3 patients with allergic contact dermatitis established that the allergens were menthol and trace
components such as piperitone or pulegone.
A triple-blind clinical trial involved 96 randomly selected subjects (47 cases and 49 controls; all pregnant women)
with a diagnosis of pruritus gravidarum.58 The case and control subjects were instructed to consume 60 ml of peppermint oil
(0.5% in sesame oil) and identical placebos, respectively, twice per day for 2 weeks. The authors noted that Mentha Piperita
(Peppermint) Oil did not cause any special side effects in any of the subjects tested.
Each of 6 pediatric patients with irritable bowel syndrome received a single oral dose of Mentha Piperita
(Peppermint) Oil (187 mg).59 Each capsule contained 83 mg of menthol as a constituent of Mentha Piperita (Peppermint) Oil.
Each patient drank 125 ml of water after ingestion of the capsule. No adverse events were reported. The delayed appearance
of menthol in the plasma was reported; a substantial lag time (range 1 h to 4 h) was observed in all subjects. Thus, an
apparent prolonged absorption time was demonstrated. The authors noted that reasons for the delayed time of peak (Tmax)
likely related to formulation-specific factors (ie, delayed release) and, potentially, enterohepatic recirculation.
Menthol
When 877 patients with primary contact, atopic, nummular, and stasis dermatitis and eczema were tested with 5%
menthol in yellow paraffin, reactions were observed in 1% of the panelists within 96 h.1
SUMMARY
The safety of the following ingredients in cosmetics has been reviewed by the Cosmetic Ingredient Review (CIR)
Expert Panel (Panel), and a final report with a conclusion stating that these ingredients are safe as used in cosmetic
formulations was published in 2001: Mentha Piperita (Peppermint) Oil, Mentha Piperita (Peppermint) Leaf Extract, Mentha
Piperita (Peppermint) Leaf, and Mentha Piperita (Peppermint) Leaf Water. The current safety assessment is a re-review of the
4 Mentha Piperita (Peppermint)-derived ingredients, and is inclusive of safety test data that have become available since the
final report was issued.
The following Mentha Piperita (Peppermint)-derived ingredients are reviewed in this safety assessment: Mentha
Piperita (Peppermint) Oil, Mentha Piperita (Peppermint) Leaf Extract, Mentha Piperita (Peppermint) Leaf, and Mentha
Piperita (Peppermint) Leaf Water. These ingredients function mostly as fragrance ingredients and skin conditioning agents in
cosmetic products.
According to 2017 VCRP data, the greatest use frequency is being reported for Mentha Piperita (Peppermint) Oil,
which is being used in 827 cosmetic products, mostly leave-on products. The results of a concentration of use survey
provided in 2016 indicate that Mentha Piperita (Peppermint) Leaf Water is being used at concentrations up to 15% in leave-
on products, which is the greatest use concentration that is being reported for Mentha Piperita (Peppermint)-derived
ingredients reviewed in this safety assessment.
Mentha Piperita (Peppermint) Oil is generally recognized as safe for use in food for human consumption. It is also
an inactive ingredient in drug products that have been approved by the FDA and is on the United States Environmental
Protection Agency’s list of active ingredients eligible for minimum risk pesticide products.
Mentha Piperita (Peppermint) Leaf Extract (aqueous ethanol extract) caused a statistically significant increase in the
penetration of caffeine, but not salicylic acid, through porcine skin. Mentha Piperita (Peppermint) Oil inhibited the
penetration of benzoic acid through human skin.
Following oral adminstration, Mentha Piperita (Peppermint) Oil is relatively rapidly absorbed and eliminated mainly
via the bile.4 The major biliary metabolite is menthol glucuronide. Additional metabolites are mono- or di-hydroxylated
menthol derivatives.
Mentha Piperita (Peppermint) Leaf (as Mentha piperita tea) was not nephrotoxic to rats when administered (20 g/l)
in drinking water daily for 30 days.
No adverse events were reported for single-ingredient peppermint supplements in a study that was performed to
characterize data on dietary botanical supplement (DBSs) associated with adverse event reports submitted to the FDA Center
for Food Safety and Applied Nutrition’s Adverse Event Reporting System (CAERS).
Mentha Piperita (Peppermint) Oil was clastogenic in a chromosome aberration test involving peripheral blood
lymphocytes. In a genotoxicity assay involving human lymphocytes, Mentha Piperita (Peppermint) Oil induced sister
chromatid exchanges in a dose-dependent manner.
Oral pretreatment with Mentha Piperita (Peppermint) Leaf Extract (aqueous extract) before exposure to gamma
radiation was found to be effective in protecting against chromosomal damage in the bone marrow of Swiss albino mice. In
another study, the oral administration of Mentha Piperita (Peppermint) Leaf extract had an antigenotoxic (i.e., reduced the
frequency of chromosomal aberrations and micronuclei in bone marrow cells) in Swiss albino mice intraperitoneally injected
with benzo(a)pyrene.
In a 2-year bioassay, pulegone was administered to groups of 50 male and 50 female F344/N rats and groups of 50
male and 50 female B6C3F1 mice by corn oil gavage (5 days/week). Increased incidences of liver neoplasms in male and
female B6C3F1 mice in the study led to the conclusion that there was clear evidence of carcinogenic activity in mice. For
female F344/N rats, it was concluded that there was some evidence of carcinogenicity based on an increased incidence of
urinary bladder neoplasms. Male rats did not have increased incidences of bladder tumors or neoplasms of other organs.
Oral dosing with Mentha Piperita (Peppermint) Leaf Extract caused a significant reduction in the number of lung
adenomas from an incidence of 67.92% in Swiss albino mice intraperitoneally injected with benzo(a)pyrene to 26.31%. Oral
dosing with Mentha Piperita (Peppermint) Leaf Extract also caused inhibition of skin papilloma formation induced by
DMBA and the application of croton oil, in terms of a significant decrease in the cumulative number of papillomas, tumor
burden, and tumor incidence.
In the human cancer cell lines tested with Mentha Piperita (Peppermint) Leaf Extract (various extractants used), the
number of apoptotic cells was incremental with an increase in the dose of Mentha piperita extracts. Mentha Piperita
(Peppermint) Leaf Extract (only from chloroform and ethyl acetate extractants) had significant dose- and time-dependent
anticarcinogenic activity, leading to G1 cell cycle arrest and mitochondrial-mediated apoptosis, perturbation of oxidative
balance, upregulation of Bax gene, and elevated expression of p53 and p21 in the treated cells. In a study that was performed
to evaluate the antitumor activity of Mentha Piperita (Peppermint) Leaf Extract (methanol extract) in an anti-proliferation
assay involving SW-480 human colon adenocarcinoma cells, statistically significant growth inhibition was observed.
Results were positive for Mentha Piperita (Peppermint) Oil was in cytotoxicity assays involving human cancer cell
lines.
Mentha Piperita (Peppermint) Leaf Extract (methanol extract) did not induce hepatotoxicity in in vitro assays
involving human (HepG2/C3A) and rat (MH1C1) hepatoma cells.
The 50% ethanol extract of peppermint leaves and stems significantly inhibited compound 48/80-induced histamine
release from rat peritoneal mast cells in vitro.
In a study involving C57BL/6 mice, it was concluded that 3% Mentha Piperita (Peppermint) Oil (diluted in jojoba
oil) facilitated hair growth by promoting the conservation of vascularization of hair dermal papilla.
A face cream containing 20% Mentha Piperita (Peppermint) Leaf Water did not induce cumulative skin irritation or
sensitization in an HRIPT involving 107 subjects. Slight erythema was observed in 1 of 50 subjects who applied a cleansing
gel containing 50% Mentha Piperita (Peppermint) Leaf Water twice per day for 4 weeks; there were no signs of ocular or
palpebral irritation in any of the subjects. In a 48-h, single-application patch test, the skin irritation potential of a cleansing
gel containing 50% Mentha Piperita (Peppermint) Leaf Water (10% aqueous dilution [effective concentration = 5%]) was
evaluated using 52 subjects. A score of 1 (mild erythema) was reported for 12 subjects on day 2 and for 18 subjects on day 3.
A score of 2 (moderate erythema) was reported for 2 subjects on day 2 and for 3 subjects on day 3. On day 4, 46 subjects had
a score of 0 and 6 had a score of 1. The authors concluded that the skin compatability of the diluted product was considered
good.
In a multicenter study, neither irritant nor allergic reactions were observed in 73 patients patch tested with Mentha
Piperita (Peppermint) Oil according to ICDRG patch test procedures.
Mostly positive patch test reactions to Mentha Piperita (Peppermint) Oil (2%in petrolatum) and Mentha Piperita
were reported in case reports on patients with diseased skin. In patients without skin disease, but with peppermint sensitivity,
positive prick test reactions to Mentha Piperita (Peppermint) Leaf, Mentha Piperita (Peppermint) Leaf Extract, and Mentha
Piperita were reported. In other clinical reports, oral dosing with Mentha Piperita (Peppermint) Oil (0.5% in sesame oil, 60
ml) did not cause any side effects in 47 pregnant female patients. A single oral dose of Mentha Piperita (Peppermint) Oil did
not cause any adverse events in 6 pediatric patients.
DISCUSSION (From 2001 Report)
In assessing the safety of Peppermint (Mentha Piperita) Oil, Peppermint (Mentha Piperita) Extract, Peppermint
(Mentha Piperita) Leaves, and Peppermint (Mentha Piperita) Water, the CIR Expert Panel was concerned about oral-dosing
studies that reported cyst-like spaces in the cerebellum of rats. The results of these studies were difficult to interpret. The
findings were not consistent among studies (lesions were noted in some studies but not others), and though the lesions
appeared to depend on the pulegone content, no definitive conclusion could be made (a greater NOAEL was reported in a
90-day study using a Peppermint Oil containing 1.1% pulegone versus a 28-day study that tested a Peppermingt Oil
containing 1.7% pulegone). The Panel also noted that the large differences between doses within each study made it
impossible to pinpoint exactly the dose at which changes first appeared.
Noting the lack of dermal exposure studies on Peppermint Oil, the Panel expected its absorption would be rapid,
following that of menthol, a major component. Dermal absorption, however, was not expected to be greater than absorption
through the gastrointestinal tract. Metabolism from either route of exposure would be similar – phase 1 metabolism followed
by transport to the liver. The Panel was of the opinion that the oral-dose data contained in this report were sufficient to
address concerns resulting from the expected rapid absorption. However, the Panel noted the evidence that menthol can
enhance penetration. Formulators are cautioned that this enhanced penetration can affect the use of other ingredients whose
safety assessment was based on their lack of absorption.
Clinical dermal testing demonstrated that 8% Peppermint Oil was not a sensitizer, and that 2% Peppermint Oil
produced a small number of positive reactions in dermatitis patients.
Because pulegone is toxic, the Panel limited it to ≤ 1% in cosmetic grade Peppermint (Mentha Piperita) Oil,
Peppermint (Mentha Piperita) Extract, Peppermint (Mentha Piperita) Leaves, and Peppermint (Mentha Piperita) Water.
The Panel was confident that this concentration was achievable both by controlling the time of harvest, and through the
patented technique described in this report. Recent data reported that Peppermint (Mentha Piperita) Oil is used at a
concentration of ≤ 3% in rinse-off formulations and ≤ 0.2% in leave-on formulations. This concentration of use data coupled
with the ≤ 1% restriction on pulegone suggested to the Panel that pulegone toxicity would not be seen with cosmetic use.
Table 1. Definitions and Functions of the Ingredients in this Safety Assessment.(2; [CIR Staff])
Ingredient CAS No. Definition & Idealized Structures Function
Mentha Piperita (Peppermint) Oil Mentha Piperita (Peppermint) Oil is a volatile oil obtained from the whole plant Fragrance
Mentha piperita. The accepted scientific name for Mentha piperita is Mentha x Ingredients; Skin-
piperita. Conditioning
Agents -
Miscellaneous
Mentha Piperita (Peppermint) Leaf Extract Mentha Piperita (Peppermint) Leaf Extract is the extract of the leaves of the Fragrance
peppermint, Mentha piperita. The accepted scientific name for Mentha piperita Ingredients; Skin-
is Mentha x piperita. Conditioning
Agents -
Miscellaneous;
Skin-
Conditioning
Agents -
Occlusive
Mentha Piperita (Peppermint) Leaf Mentha Piperita (Peppermint) Leaf is the dried leaves of Mentha piperita. The Fragrance
accepted scientific name for Mentha piperita is Mentha x piperita. Ingredients
Mentha Piperita (Peppermint) Leaf Water Mentha Piperita (Peppermint) Leaf Water is an aqueous solution of the steam Flavoring Agents;
distillate obtained from the leaves of Mentha piperita. The accepted scientific Fragrance
name for Mentha piperita is Mentha x piperita. Ingredients; Skin-
Conditioning
Agents -
Miscellaneous
Mentha Piperita (Peppermint) Extract Mentha Piperita (Peppermint) Extract is the extract of the whole plant, Skin-
Mentha piperita. The accepted scientific name for Mentha piperita is Mentha Conditioning
x piperita. Agents -
Miscellaneous
Mentha Piperita (Peppermint) Mentha Piperita (Peppermint) Flower/Leaf/Stem Extract is the extract of Flavoring
Flower/Leaf/Stem Extract the flowers, leaves and stems of Mentha piperita. The accepted scientific Agents; Fragran
name for Mentha piperita is Mentha x piperita. ce
Ingredients; Ski
n-Conditioning
Agents -
Miscellaneous
Mentha Piperita (Peppermint) Mentha Piperita (Peppermint) Flower/Leaf/Stem Water is the aqueous Fragrance
Flower/Leaf/Stem Water solution of the steam distillates obtained from the flowers, leaves and stems Ingredients
of Mentha piperita. The accepted scientific name for Mentha piperita is
Mentha x piperita.
Mentha Piperita (Peppermint) Leaf Cell Mentha Piperita (Peppermint) Leaf Cell Extract is the extract of a culture Antioxidants; Sk
Extract of the leaf cells of Mentha piperita. The accepted scientific name for Mentha in Protectants
piperita is Mentha x piperita.
Mentha Piperita (Peppermint) Leaf Juice Mentha Piperita (Peppermint) Leaf Juice is the juice expressed from the Skin-
leaves of Mentha piperita. The accepted scientific name for Mentha piperita Conditioning
is Mentha x piperita. Agents -
Miscellaneous
Mentha Piperita (Peppermint) Meristem Mentha Piperita (Peppermint) Meristem Cell Culture is a suspension of the Skin-
Cell Culture cultured meristem cells of Mentha piperita. The accepted scientific name for Conditioning
Mentha piperita is Mentha x piperita. Agents -
Miscellaneous
Table 2. Physical and Chemical Properties of Mentha Piperita (Peppermint) Oil

Property Value Reference
Form Colorless or pale yellow liquid 1
Angular rotation (˚C) Between -18 and 32 1
Refractive index (at 20˚C) Between 1.459 and 1.465 1
Specific gravity Between 0.896 and 0.908 1
Assay for total esters Not less than 5% of esters, calculated as menthyl acetate 1
Assay for total menthol Not less than 50% of menthol 1
Dimethyl sulfide Passes test (rectified); fails test (natural) 1
Heavy metals (as Pb) Passes test (limit of 0.004%) 1
Solubility Soluble in alcohol: Passes test (1 volume dissolves in 3 volumes of 70% alcohol); 1
Soluble in most vegetable oils; insoluble in propylene glycol 7
Table 3. Frequency and Concentration of Use of Mentha Piperita (Peppermint)-derived Ingredients According to Duration and Exposure.1,14,15
# of Uses Max Conc of Use (%) # of Uses Max Conc of Use (%)
Mentha Piperita (Peppermint) Oil Mentha Piperita (Peppermint) Leaf Extract
2017 1998 2017 1997 2017 1997 2017 1997
Totals* 827 102 0.0001-5 0.1-3 198 35 0.000075-0.5 NR
Duration of Use
Leave-On 433 52 0.0006-5 0.2-2 118 10 0.000075-0.5 NR
Rinse-Off 360 44 0.0001-1.9 0.1-3 79 24 0.0001-0.2 NR
Diluted for (Bath) Use 34 6 0.018-3.9 NR 1 1 NR NR
Exposure Type
Eye Area 4 NR 0.00094 NR 4 NR 0.0018 NR
Incidental Ingestion 214 24 0.05-2.9 0.2-1.2 7 NR 0.00075-0.5 NR
a a a a
Incidental Inhalation-Spray 19;120 NR;23 0.017-1;0.002- NR 5;34 NR;2 0.00041- NR
1.1a 0.0046;0.00057-
0.026a
Incidental Inhalation-Powder 1a NR 0.01-1 NR 3 NR 0.0018 NR
Dermal Contact 458 75 0.0006-5 0.1-2 139 22 0.000075-0.2 NR
Deodorant (underarm) 2 NR NR NR NR NR 0.0018 NR
Hair - Non-Coloring 148 1 0.0001-0.96 3 50 13 0.00018-0.2 NR
Hair-Coloring NR NR 0.0024 NR NR NR 0.032 NR
Nail 7 2 0.00064-1.5 NR 2 NR NR NR
Mucous Membrane 317 30 0.0025-3.9 0.2-1.2 8 6 0.00075-0.5 NR
Baby Products 1 NR 0.2 NR NR NR NR NR
Mentha Piperita (Peppermint) Leaf Mentha Piperita (Peppermint) Leaf Water
2017 1998 2017 1997 2017 1998 2017 1997
Totals* NR NR 0.0002-1.6 NR 15 NR 0.00013-15 NR
Duration of Use
Leave-On NR NR 0.001 NR 9 NR 0.00013-15 NR
Rinse-Off NR NR 0.0002-1.6 NR 6 NR 0.00021-0.00067 NR
Diluted for (Bath) Use NR NR NR NR NR NR NR NR
Exposure Type
Eye Area NR NR NR NR 2 NR NR NR
Incidental Ingestion NR NR NR NR NR NR NR NR
a a a
Incidental Inhalation-Spray NR NR NR;0.001 NR NR;4 NR NR;0.00043-10 NR
Incidental Inhalation-Powder NR NR NR NR NR NR NR NR
Dermal Contact NR NR 0.001-1.6 NR 13 NR 0.00013-15 NR
Deodorant (underarm) NR NR NR NR 1 NR 15 NR
Hair - Non-Coloring NR NR 0.0002-0.023 NR NR NR NR NR
Hair-Coloring NR NR NR NR NR NR NR NR
Nail NR NR NR NR NR NR NR NR
Mucous Membrane NR NR 0.001-0.16 NR NR NR NR NR
Baby Products NR NR NR NR NR NR NR NR
Peppermint
2017 1998 2017 1997
Totals* NR 2 NS NR
Duration of Use
Leave-On NR 1 NS NR
Rinse-Off NR NR NR NR
Diluted for (Bath) Use NR 1 NS NR
Exposure Type
Eye Area NR NR NS NR
Incidental Ingestion NR NR NS NR
Incidental Inhalation-Spray NR NR;1a NS NR
Incidental Inhalation-Powder NR NR NS NR
Dermal Contact NR 2 NS NR
Deodorant (underarm) NR NR NR NR
Hair - Non-Coloring NR NR NS NR
Hair-Coloring NR NR NS NR
Nail NR NR NS NR
Mucous Membrane NR 1 NS NR
Baby Products NR NR NS NR
*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 are sprays, but it is not specified whether the reported uses are sprays..
NR - no reported use
NS - not surveyed
Table 4. Human Dermal Irritation and Sensitization Data

Ingredient Number of Subjects Protocol Results
Irritation Studies
50% Mentha Piperita 50 subjects Subjects applied product twice Slight erythema was observed in
(Peppermint) Leaf Water in per day for 4 weeks, and were one subject.45
a cleansing gel instructed to record any signs
felt or observed during product
use.
50% Mentha Piperita 52 subjects Diluted product applied, under A score of 1 (mild erythema)
(Peppermint) Leaf Water in occlusive patch, to the skin for was reported for 12 subjects on
a cleansing gel (10% 48 h. Reactions scored up to day 2 and for 18 subjects on day
aqueous dilution [effective 48 ± 4 h after patch removal 3. A score of 2 (moderate
concentration = 5%]) (day 4). erythema) was reported for 2
subjects on day 2 and for 3
subjects on day 3. On day 4, 46
subjects had a score of 0 and 6
had a score of 1. Skin
compatability of diluted product
considered good.46
Sensitization Studies
20% Mentha Piperita 107 subjects (96 women, In human repeated insult patch Product did not induce
(Peppermint) Leaf Water in 11 men) with no history test (HRIPT), product applied cumulative irritation or
a face cream of atopy (0.02 ml) to the back using sensitization.47
occlusive patch (small Finn
chamber), and 9 induction
applications made over 3-week
period. For 1st, 2nd, 5th, 7th,
and 8th applications, duration
of exposure was 48 ± 4 h.
Duration of exposure was 72 ±
4 h for 3rd, 6th, and 9th
applications. Challenge phase
consisted of single application
to new site and a previously
treated site for 48 ± 4 h.
Mentha Piperita 73 patients Multicenter study Neither irritant nor allergic

(Peppermint) Oil (dermatology clinics in reactions reported.48
(concentration not stated) Finland). Patients patch tested
according to International
Contact Dermatitis Research
Group (ICDRG) patch test
procedures during 1994 to
1998
Case Reports
Mentha Piperita Male patient with Patch test Allergic positive reaction.49
(Peppermint) Oil (2% in orofacial granulomatosis
petrolatum) mainly affecting lower
lip
Mentha Piperita Female patient with Patch and prick tests Positive patch test reaction, i.e.,
(Peppermint) Oil lichenoid eruption on itching, erythema, and swelling,
(concentration not stated) oral mucosa beginning at day 5; ++ reaction
by day 7. Prick test results
negative.50
Mentha Piperita Male patient with Patch test Strong positive reactions to
(Peppermint) Oil (2% in history of hand eczema LAT patch and to Mentha
petrolatum) and sensitization to Piperita (Peppermint) Oil (2% in
tixocortol pivalate. petrolatum).51
Presented with severe
eczematous contact
dermatitis after repeated
applications of a local
action transcutaneous
(LAT) patch for lumbar
pain containing Mentha
Piperita (Peppermint)
Oil.
Table 4. Human Dermal Irritation and Sensitization Data

Ingredient Number of Subjects Protocol Results
Mentha Piperita Female patient with Patch test. Reactions evaluated Positive patch test reaction (+
(Peppermint) Oil (2% in allergic contact at 2, 3 ,and 7 days according to reaction) observed on days 2 and
petrolatum) dermatitis after ICDRG procedures. 3.52
consuming herbal tea
containing Mentha
Oil.
Mentha Piperita 4 patients with allergic Patch test. Reactions evaluated Positive patch test reactions to
(Peppermint) Oil contact cheilitis (lips and at 48 h and 96 h. lip balm and to Mentha Piperita
(concentration not stated) perioral skin), secondary (Peppermint) Oil.53
to exposure to lip balm
that contained Mentha
Oil
Mentha Piperita Male patient with IgE- Skin prick and prick-to-prick Patient had strongly positive
(Peppermint) Leaf and mediated anaphylaxis to tests prick test reaction to slurry of
Peppermint (concentration peppermint (Mentha peppermint candy and fresh
not stated) piperita) after sucking peppermint leaf. Prick testing of
on peppermint candy. 5 patient with saline slurry of
healthy controls peppermint candy caused wheal
and flare, with largest diameters
of 10 mm and 35 mm
(W10/F25), respectively. Prick-
to-prick test with fresh
peppermint leaf revealed skin
test response of W25/F50. All
prick tests on 5 controls
negative.56
Mentha Piperita Female patient became Skin prick test Positive skin prick test reaction
(Peppermint) Leaf Extract symptomatic with to commercial Mentha Piperita
(concentration not stated) dyspnea when near (Peppermint) Leaf Extract.57
peppermint (Mentha
piperita) scent
Mentha Piperita Male patient with severe Patch test Negative reaction..54
(Peppermint) (concentration cheilitis
not stated)
Mentha Piperita Female patient with Patch test + reaction on days 2 and 4.55
(Peppermint) fragrance recurrent irritant rash
(1:50, 2% in petrolatum) after applying a Mentha
foot spray
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2017 FDA VCRP Data

01B - Baby Lotions, Oils, Powders, and Creams 1
02A - Bath Oils, Tablets, and Salts 24
02B - Bubble Baths 2
02D - Other Bath Preparations 8
03G - Other Eye Makeup Preparations 4
04B - Perfumes 1
04E - Other Fragrance Preparation 17
05A - Hair Conditioner 43
05B - Hair Spray (aerosol fixatives) 1
05F - Shampoos (non-coloring) 57
05G - Tonics, Dressings, and Other Hair Grooming Aids 31
05H - Wave Sets 1
05I - Other Hair Preparations 15
07E - Lipstick 88
07I - Other Makeup Preparations 34
08B - Cuticle Softeners 2
08E - Nail Polish and Enamel 2
08G - Other Manicuring Preparations 3
09A - Dentifrices 34
09B - Mouthwashes and Breath Fresheners 19
09C - Other Oral Hygiene Products 73
10A - Bath Soaps and Detergents 43
10B - Deodorants (underarm) 2
10E - Other Personal Cleanliness Products 26
11A - Aftershave Lotion 3
11B - Beard Softeners 2
11D - Preshave Lotions (all types) 2
11E - Shaving Cream 10
11G - Other Shaving Preparation Products 2
12A - Cleansing 33
12C - Face and Neck (exc shave) 30
12D - Body and Hand (exc shave) 45
12E - Foot Powders and Sprays 9
12F - Moisturizing 56
12G - Night 1
12H - Paste Masks (mud packs) 17
12I - Skin Fresheners 13
12J - Other Skin Care Preps 73
Total 827
Mentha Piperita (Peppermint) Leaf (No Posting)

02D - Other Bath Preparations 1
03D - Eye Lotion 4
04C - Powders (dusting and talcum, excluding aftershave

talc) 1
04E - Other Fragrance Preparation 4
05A - Hair Conditioner 23
05B - Hair Spray (aerosol fixatives) 1
05F - Shampoos (non-coloring) 18
05G - Tonics, Dressings, and Other Hair Grooming Aids 3
05I - Other Hair Preparations 5
07B - Face Powders 2
07C - Foundations 2
07D - Leg and Body Paints 1
07E - Lipstick 5
07I - Other Makeup Preparations 2
08F - Nail Polish and Enamel Removers 1
08G - Other Manicuring Preparations 1
09A - Dentifrices 1
09B - Mouthwashes and Breath Fresheners 1
10E - Other Personal Cleanliness Products 6
11A - Aftershave Lotion 3
12A - Cleansing 14
12D - Body and Hand (exc shave) 5
12E - Foot Powders and Sprays 1
12G - Night 2
13A - Suntan Gels, Creams, and Liquids 1
Total 198

03G - Other Eye Makeup Preparations 2
10B - Deodorants (underarm) 1
12A - Cleansing 3
Total 15
Memorandum
TO: Lillian Gill, D.P.A.

Director - COSMETIC INGREDIENT REVIEW (CIR)
FROM: Beth A. Lange, Ph.D.

Industry Liaison to the CIR Expert Panel
DATE: March 1, 2016
SUBJECT: Concentration of Use by FDA Product Category: Peppermint-Derived Ingredients

Concentration of Use by FDA Product Category – Peppermint-Derived Ingredients
Mentha Piperita (Peppermint) Oil Mentha Piperita (Peppermint) Leaf

Mentha Piperita (Peppermint) Leaf Extract Mentha Piperita (Peppermint) Leaf Water
Ingredient Product Category Maximum
Concentration of Use
Mentha Piperita (Peppermint) Oil Baby lotions, oils and creams
Not powder (1B) 0.2%
Mentha Piperita (Peppermint) Oil Bath oils, tablets and salts (2A) 3.9%
Mentha Piperita (Peppermint) Oil Other bath preparations (2D) 0.018%
Mentha Piperita (Peppermint) Oil Eye lotions (3D) 0.00094%
Mentha Piperita (Peppermint) Oil Hair conditioners (5A) 0.0001-0.33%
Mentha Piperita (Peppermint) Oil Hair sprays (5B)
Aerosol 0.017%
Pump spray 0.017-0.02%
Mentha Piperita (Peppermint) Oil Rinses (noncoloring) (5E) 0.02%
Mentha Piperita (Peppermint) Oil Shampoos (noncoloring) (5F) 0.0001-0.75%
Mentha Piperita (Peppermint) Oil Tonics, dressings and other hair grooming 0.002-0.96%
aids (5G)
Mentha Piperita (Peppermint) Oil Wave sets (5H) 0.01%
Mentha Piperita (Peppermint) Oil Other hair preparations (noncoloring) (5I) 0.0033-0.05%
Mentha Piperita (Peppermint) Oil Hair dyes and colors (6A) 0.0024%
Mentha Piperita (Peppermint) Oil Foundations (7C) 0.0006%
Mentha Piperita (Peppermint) Oil Lipstick (7E) 0.05-2.9%
Mentha Piperita (Peppermint) Oil Makeup bases (7F) 0.005%
Mentha Piperita (Peppermint) Oil Basecoats and undercoats (8A) 0.00064%
Mentha Piperita (Peppermint) Oil Cuticle softeners (8B) 1.5%
Mentha Piperita (Peppermint) Oil Other manicuring preparations (8G) 0.2-0.45%
Mentha Piperita (Peppermint) Oil Dentifrices (9A) 0.95%
Mentha Piperita (Peppermint) Oil Mouth washes and breath fresheners (9B) 0.11-1.1%
Mentha Piperita (Peppermint) Oil Other oral hygiene products (9C) 0.22-1.3%
Mentha Piperita (Peppermint) Oil Bath soaps and detergents (10A) 0.0034-1.9%
Mentha Piperita (Peppermint) Oil Other personal cleanliness products (10E) 0.0025-1.1%
Mentha Piperita (Peppermint) Oil Aftershave lotions (11A) 0.003%
Mentha Piperita (Peppermint) Oil Shaving cream (11E) 0.4-0.7%
Mentha Piperita (Peppermint) Oil Skin cleansing (cold creams, cleansing 0.015-0.25%
lotions, liquids and pads) (12A)
Mentha Piperita (Peppermint) Oil Face and neck products
Not spray (12C) 0.01-5%
Mentha Piperita (Peppermint) Oil Body and hand products (12D)
Not spray 0.05-2.3%
Spray 0.006-0.3%
Mentha Piperita (Peppermint) Oil Foot powders and sprays (12E) 0.01-1%
Spray 0.5%
Mentha Piperita (Peppermint) Oil Moisturizing products (12F)
Not spray 0.006%
Mentha Piperita (Peppermint) Oil Paste masks and mud packs (12H) 0.01-0.011%
Mentha Piperita (Peppermint) Oil Skin fresheners (12I) 0.1-0.12%
Mentha Piperita (Peppermint) Oil Other skin care preparations (12J) 0.1-0.22%
Mentha Piperita (Peppermint) Leaf Eye lotions (3D) 0.0018%
Extract
Mentha Piperita (Peppermint) Leaf Hair conditioners (5A) 0.0005-0.2%
Extract
Mentha Piperita (Peppermint) Leaf Hair sprays (5B)
Extract Aerosol 0.00041%
Pump 0.0046%
Mentha Piperita (Peppermint) Leaf Rinses (noncoloring) (5E) 0.00088%
Extract
Mentha Piperita (Peppermint) Leaf Shampoos (noncoloring) (5F) 0.00018-0.2%
Extract
Mentha Piperita (Peppermint) Leaf Tonics, dressings and other hair grooming 0.00057-0.001%
Extract aids (5G)
Mentha Piperita (Peppermint) Leaf Hair tints (6B) 0.032%
Extract
Mentha Piperita (Peppermint) Leaf Face powders (7B) 0.0018%
Extract
Mentha Piperita (Peppermint) Leaf Foundations (7C) 0.0018%
Extract
Mentha Piperita (Peppermint) Leaf Lipstick (7E) 0.5%
Extract
Mentha Piperita (Peppermint) Leaf Makeup bases (7F) 0.00018%
Extract
Mentha Piperita (Peppermint) Leaf Mouth wash and breath fresheners (9B) 0.00075%
Extract
Mentha Piperita (Peppermint) Leaf Bath soaps and detergents (10A) 0.0018%
Extract
Mentha Piperita (Peppermint) Leaf Deodorants (10B)
Extract Pump spray 0.0018%
Mentha Piperita (Peppermint) Leaf Other personal cleanliness products (10E) 0.002%
Extract
Mentha Piperita (Peppermint) Leaf Aftershave lotions (11A) 0.0018%
Extract
Mentha Piperita (Peppermint) Leaf Skin cleansing (cold creams, cleansing 0.0001-0.18%
Extract lotions, liquids and pads) (12A)
Mentha Piperita (Peppermint) Leaf Face and neck products (12C)
Extract Not spray 0.000075-0.05%
Spray 0.001%
Mentha Piperita (Peppermint) Leaf Body and hand products (12D)
Spray 0.001%
Mentha Piperita (Peppermint) Leaf Moisturizing products (12F)
Mentha Piperita (Peppermint) Leaf Other skin care preparations (12J) 0.0012%
Extract
Mentha Piperita (Peppermint) Leaf Indoor tanning preparations (13B) 0.026%
Extract
Mentha Piperita (Peppermint) Leaf Hair conditioners (5A) 0.023%
Mentha Piperita (Peppermint) Leaf Shampoos (noncoloring) (5F) 0.0002%
Mentha Piperita (Peppermint) Leaf Tonics, dressings and other hair grooming 0.001%
aids (5G)
Mentha Piperita (Peppermint) Leaf Bath soaps and detergents (10A) 0.001-0.16%
Not spray 0.001%
Mentha Piperita (Peppermint) Leaf Paste masks and mud packs (12H) 1.6%
Mentha Piperita (Peppermint) Leaf Foundations (7C) 0.00013%
Water
Mentha Piperita (Peppermint) Leaf Deodorants (10B)
Water Not spray 15%
Mentha Piperita (Peppermint) Leaf Shaving cream (11E) 0.00021%
Water
Mentha Piperita (Peppermint) Leaf Skin cleansing (cold creams, cleansing 0.00067%
Water lotions, liquids and pads) (12A)
Water Not spray 0.00067-40%
Mentha Piperita (Peppermint) Leaf Body and hand products (12D)
Water Not spray 0.00018-15%
Mentha Piperita (Peppermint) Leaf Moisturizing products (12F)
Water Not spray 10%
Mentha Piperita (Peppermint) Leaf Indoor tanning preparations (13B) 0.00043%
Water
Information collected 2015-2016
Table prepared February 29, 2016
Personal Care Products Council

Committed to Safety,
Quality & Innovation
Memorandum
TO: Lillian Gill, D.P.A.

Director COSMETIC INGREDIENT REVIEW (CIR)
-
FROM: Beth A. Lange, Ph.D.

Industry Liaison to the CIR Expert Panel
DATE: March 1,2016
SUBJECT: Mentha Piperita (Peppermint) Leaf Water
Institut d’Expertise Clinique. 2010. Sensitisation and cutaneous compatibility study (face cream
containing 20% Mentha Piperita (Peppermint) Leaf Water).
Peritesco. 2008. Ocular and cutaneous acceptability study of a cleansing gel (containing 50%
Mentha Piperita (Peppermint) Leaf Water) during 4 weeks under ophthalmological and
dermatological control.
4-Front Research. 2007. Single patch test of a cleansing gel containing 50% Mentha Piperita
(Peppermint) Leaf Water.
1620 L Street, N.W., Suite 1200 Washington, D.C. 20036 202.331.17701 202.331.1969 (fax) www.personalcarecoundl.org
FRANCE
ismimm
d EXPERTISE
CLI [‘ii 0 ti 6
J.E.C. BULGARIE
REPORT: SENSITISATION AND

CUTANEOUS COMPATIBILITYSTUDY
DT036460
VERIFICATION OF ThE ABSENCE OF SENSITIS[NG POTENTIAL AND OF THE

GOOD CUTANEOUS COMPATIBILITY OF A COSMETIC INVESTIGATIONAL
PRODUCT, BY REPEATED EPICUTANEOUS APPLICATIONS UNDER OCCLUSIVE
PATCR IN 110 (OR 108, OR 107) HEALTHY ADULT SUBJECTS
(modified Manulli and Maibach method)
INVESTIGATIONAL
PRODUCT
MENTHA PIPERITA (PEPPERMINT) LEAF WATER 20% Face Cream -
batch n•NCFI du 12/jart’20I0)

PROTOCOLS Specific W BIOO3IOPE, of25 March 2010 refers to
Standard W ENPSTD_CLITP_5021_01, of 20 January 2005
REPORT N° BIOO3IORD7 —version I of 18 June 2010
BEGINNING OF THE
OBSERVATIONS 30 March 2010
END OF OBSERVATIONS 8 May2010
SAFETY ASSESSOR DEPUTY TECHNICAL AND DERMATOLOGISTS

SCIENTIFIC MANAGER
Miss E. ATANASSOVA -Dr. Z. PANOVk M.D.
Engineer in Biotechnology, Unvesugator,)
Master in Biotechnology - Dr. G. BOCHEVA. M.D.
I.E.C. Buigarie Investigating Laboratory:
Lozenetz I 6A, Kichinev Street
- 1.E.C. Bulgarie
1407 SOFIA- BULGARIA Lozenetz- bA, Kichinev Street
I 1407 SOFIA- BULGARIA
Document ofóO pages
88, Sd des Belges 69006 LYON FRANCE
IeI .33 CI .172 GO 8900 F +33 (0(4 72 60 09 67 emad uIe:ier,trnnre rem

www.iecfrance.com
Report No B I 0031 ORD7 Version I

- Ige 4/60
AUTH ENTICATON
The study subject of the present report was conducted under my responsibility, in compliance with
standard and specific study protocols, in accordance with I.E.C. Standard Operating Procedures and in
the spirit of the general principles of the Good Clinical Practices (ICH topic E 6- CPMP!ICH/135/95).
I sstzm the responsibility of the validity of all raw data obtained during this study and mentioned in
the present report.
Dr. Zoya PANOVA, M.D.

Dermatologist Investigator
I have read this report, Itify that these data are an accurate reflection of the results obtained and
I agree with its content.
jA1O1°
Elitsa ATANASSOVA
Deputy Technical and Scientific Manager
Report N” BIOO3IORD7- Version I Page 5/60
PERSONNEL INVOLVED IN THE REALISATION OF THE STUDY

(for 1K C. France,)
President General Director D ep uty General Director- Vice-President

Name: JP. GUILLOT Name: E. CAMEL
Senior Toxicologist Pharmacologist
- Pharm. D., D.E.A. in Skin Biology and
(Eurotox Registered Toxicologist) Cosm dology, Senior Toxicologist
Address: Route de Bibost (Eurotox Registered Toxicologist)
69690 Bessenay France
- Address: 88, boulevard des Belges
+33 (0) 4.74.70.93.39 69006 Lyon- France
33 (0) 4.72.69.89.61
Administration, Finance and Human Resources Deguty General Director- Vice-President,

Director in charge of Ogerations Management
Name: Y. PDHLMANN Name: F. GUJLLOT
DUEL. in English Toxicologist, Masters in Management
Address: 88, boulevard des Belges and International Law
69006 Lyon- France Address: 88, boulevard des Belges
±33 (0) 4.72.69.70.91 69006 Lyon- France
±33 (0) 1.72.69.89.77
Head of Studies Management gerfonned at Reseonsible for the Study

LE.C. Bulgarie Name: N. RENTERO
Name: J.R. CAMPOS Ph. D. in Physiology, Industrial and Agribusiness
Graduate in Demiocosmetology Biochemistry Engineer
Doctor of Cellular Biology and Microbiology Address: 88, boulevard des Belges
Address: 88, boulevard des Belges 69006 Lyon- France
69006 Lyon- France = +33 (0) 4.72.69.71.05
—33 (0) 4.72.69.89.66
Report N” 310031 0RD7 — Version I Page 6/60
(for IE. C. Bidgarie)
Executive Director Laboratory Director Technical and Scientific

Name: G. VELEY Manager
Master in Economics and International Trade Name: N. ATANASSOVA
Address: Lozenetz 16A, Kichinev Street
- Chemical Engineer, Master in Industrial Chemistry
1407 Sofia Bulgaria
- Address: Lozenetz- 16A, Kichiuev Street
Z + (359) 2.868.35.82 1407 Sofia Bulgaria
-
Z + (359) 2.868.53.11
Administrative Manager Dermatologists

Name: K. CHTEREVA Names: Dr. Z. PANOVA, M.D.
Master in French (Investigator.)
Address: Lozenetz- 16A, Kichinev Street Dr. G. BOCHEVA, M.D.
1407 Sofia Bulgaria
- Graduates in Dermatology & Venerology
+ (359) 2.868.53.11 Address: Lozenetz 16A, Kichinev Street
-
1407 Sofia Bulgaria

-
+ (359)2.868.53.11
Deputy Technical and Scientific Manager

Name: E. ATANASSOVA
Engineer in Biotechnology, Master in Bioteclmology
Address: Lozenetz- 16A, Kichinev Street

1407 Sofia - Bulgaria
Z + (359) 2.868.53.11
Technicians Technicians
Names: K. RANGELOVA, Bachelor in Chemistry Names: M. KOLCHEVA, Master in Chemistry and
K. IVANOVA, Nurse Physics
A. KRASTANOVA, Master in Biology M. KAYTSANOVA, Secondary Degree in
V. STOYANOVA, Engineer in Chemistry and Biology
Biotechnology, Bachelor in Biotechnology I. GEORGIEVA, Master in Medical
M. GEORGIEVA, Master in Biology and Chemistry
Chemistry J. YORDANOVA, Chemical Engineer,
A, IVANOVA, Master in Biochemistry and Bachelor in Organic Teclmology
Microbiology P. BORANOVA, Master in Medical
Address: Lozenetz 16A, Kicb.inev Street
- Chemistry
1407 Sofia Bulgaria
- Address: Lozenetz 16A, Kichinev Street
-
+ (359) 2.868.53.11 1407 Sofia- Bulgaria

+ (359)2.868.53.11
Independent Ethical Committee

Names: Mr. G. VELEY, Executive Director l.E.C. Bulgarie
-
Dr. E. UCHEVA, Dermatologist, Clinical Investigator, Consultant I.E.C. Bulgarie

-
-Mr. G. STOIMENOV*, Law teacher in the “New Bulgarian University”, European Law,
Protection of the Human rights
-Prof. R. YANKOVA*, M.D., Ph.D. Chief of Dermatology and Allergology Depmiment,
University of Medicine “St. George” Plodiv, Bulgaria
Dr. G. MINCHEYA, M.D., Allergologist Dermatologist (.Allergology test with cosmetic
-
products and detergents), Dermatology & ‘enerology Dispensary, Sofia, Bulgaria
Members independentfiwn the Investigating Laboratniy andji—om the Study Monitor fSponsm,), who
vote/give their opinion about the study.
Report No 810031 ORD7 — Version I Page 7/60
INSTITUT D’EXPERTISE CLINIQUE

STJIZOA.aIH
Head Office: Lozenetz- 16A, Kichinev Street- 1407 Sofia- Bulgaria

Phone:+ (359) 2.868.53.11- Fax:+ (359) 2.868.44.72
ENGLISH SUMMARY OF THE REPORT
SPONSOR: INVESTIGATIONAL PRODUCT: MENTHA

PIPERITA (PEPPERMINT) LEAF WATER 20% Face
Cream- batch nCNCFI du 12/jan/2010
DT036460
SENSITISATION AND CUTANEOUS COMPATIBILITY STUDY
VERIFICATION OF THE ABSENCE OF SENSITISING POTENTIAL AND OF

THE GOOD CUTANEOUS COMPATIBILITY OF A COSMETIC
INVESTIGATIONAL PRODUCT, BY REPEATED EPICUTANEOUS
APPLICATIONS UNDER OCCLUSIVE PATCH,
IN 110 (OR 108, OR 107) HEALTHY ADULT SUBJECTS
(modified Marzulli and Maibach method)
INTRODUCTION The study consists in the application of the investigational product under maximize’
application conditions according to the modified Marzulli and Maibach method. It i
carried out on cosntic product whose safety had been assured by a toxicologist, witi
the aim to firther conflnn safety of this product which will be used by a large nunt
of consunns under nonml and reasonably foreseeable use conditions.
STUDY To confinn that the repeated application, under patch, of investigational product, on th
OWECFIVE subject’s back, does not induce an allergic reaction and to evaluate its good cutaneou
compatibility.
STUDY Cutaneous allergy is an individual phenonrnon, of immune origin, of which setting of

RELEVANCE activating 3 phases (penetration of the foreign substance in the skin and forming of Ui
allergen; developnrnt of the immune reaction; activating of the reaction, by a ne
application of the allergenic nxilecule to the skin). These 3 phases axe thus required t
check, in 50 or 100 subjects, the absence of sensitising potential of an investigation
product, and am the basis of the nrthod described by Marzulli and Maibach (protoco
in conformity to note dated 4 August 1997 of the French ‘Repression des Fraudes”
the “Federation des Industries de Ia Paifiunerie”j
Report N” BIOO3IORD7-Version I Page 8/60
INCLUSION To be eligible, each subject must satisf3’ all the criteria written in the standard stud
CRITERIA SPECIFIC protocol W: EN_P_STD_CLITP_5021_OI, of 20 January 2005 and th
90 11-IF STUDY specific following ones:
(in addition lot/ic Number of subjects: 100 subjects divided in two panels of 50 subjects receiving
criteria given in the investigational products for the first panel and investigational products for th
standard stud;’ second one (the product distribution being indicated in the application scheme of th
protocol) Case Report Form).
Selection of subjects: exclusive selection of 100 valid cases (a valid case will be
defined as a subject who has completed a full procedure (9 applications and 9 reading
during the induction phase followed by a double application (induction and virgin sites
and 2 readings during the challenge phase [or more if this is necessary in order to full:
evaluate observed reaction]).
However, a subject who has presented with significant reactions (moderate erythem;
and/or infiltration and/or papules and/or vesicles) twice during the induction phase
inducing a stop of application, but who received the challenge phase application afte
decision of the Dermatologist Investigator and the Sponsor, will be considered as a vali
case even though he had not followed the previous procedure.
Sat: female and male
Age: IS to 70 yn old (the 60-70 age hmzket slndd in exceed ICP/0 of the tota
nwrlxr ofsubjects)
Origin: Caucasian
Phototypes: I, II or Ill
Healthy subjects: 100% without ‘atopic” background.
NON-INCLUSION To be eligible, each subject must not meet any criterion written in the standard protocol
CRITERIA SPECIFIC cited above.
TO THE STUDY
(in addition to the
criteria given in the
standard study
protoco9
METHODOLOGY - Modes of application:

. area: back
. quantity: 0.02 ml over a 50 nml’ surface (occlusive patch: Small Finn Chambers 01
Scanpor), or 0.2 ml over a 4 em’ surface (semi-occlusive patch: Brady, U.S.A.), in cas
of reaction.
. conditions of application: investigational product as supplied.
.frequency and duration:
induction phase: 9 applications spread out over 3 weeks as follows:
.
1st week: Day 0 (Tuesday: I” application), Day 2 (Thursday), Day 4 (Saturday),

2r week: Day 7 (Tuesday), Day 9 (Thursday), Day I I (Saturday),
3rd week: Day 14 (Tuesday), Day 16 (Thursday), Day 18 (Saturday)
ISLI 4th 5th 7th
Duration of exposure: 48 ± 4 hours for the I11 and 8th applications
72 ± 4 hours for the week-ends (3”, 6’” and 9’’ applications).
rest phase: the subjects are not submitted to any application from Day 22
.
(Wednesday) to Day 34 (Monday) inclusive, i.e. for a 13-day period.

challenge phase: single application on 2 sites (virgin and induced sites) on
.
Day 35 (Tuesday) for 48 ± 4 hours.

NB.: the patches are removed by the Laboratory staff.
Report N” BIOO3IORD7-Version I Page 9/60
METHODOLOGY - Modes of evaluation:

, -Clinical observations: readings performed, according to the Sponsor’s specificities
(coil t)
(D2, D35, D37 and D39), by the Dermatologist Investigator:
. Induction phase: ! 5 to 30 ninies alIa tmmal oFfre putdl2s
. “challenge” phase: between 30 to 35 mm, and 48 ± 4 hours, hours afier remova
of the patches or more if this is necessary in order to fully evaluate observe
reactions.
- Grading, according to a given numerical scale (irritation scale: 0 to 4 & scale of the
International Contact Dermatitis Research Group (LC.D.R.Gj: 0 to 3 [+++]).
ANALYSIS OF THE -Determination of the Mean Irritation Index (MI!): equal to the sum of the quotation
RESULTS AND of the 9 readings of the induction phase divided by the number of subjects and o
EVALUATION readings performed.
CRITERIA - In/c ipretation of/he results obtained, under the experimental conditions adopted:
for cumulative irritation: arbitrazy classification (“non irritating”
“severely irritating”);
Classification of the investigational

M I I
‘ ‘
‘ product
lower than 0.25 non-irritant
0.25 to I not included slightly irritant
I to 2 not included moderately irritant
2 to 3 not included very irritant
3 to 4 severely irritant
for sensitising potential:

An erythema, of intensity higher than or equal to 2 during the “challenge” phase, with o
‘vithout palpable lesions, must be evaluated in the following days to detemtine if th
reaction decreases or increases in order to precise if the reaction observed is of allergica
or irritative type. A quick decrease of the reaction indicates an irritation (decrescendi
reaction). A reaction with presence of infiltration/oedema, which persists and/or whic]
increases within time generally indicates a reaction of allergical type, and additiona
studies (“rechallenge” and/or R.O.A.T.: Repeated Open Application Test) could b
performed 3 to 6 weeks after the first appearance of the challenge reaction and after al
reactions have ceased.
also on the base of the type of investigational product and the l.E.C. statistic
established on about 4.400 investigational products tested at LE.C. Bulgarie between
2003 and 2008 (positiorming of cumulative irritation and/or sensitisation in comparison
of investigational products of the same type).
Report NoB10031ORD7—Version I Page 10/60
‘RESULTS AND CONCLUSION
STUDIED POPULATION
Number of subjects recruited 137

Number of subjects who came to I.E.C. 121
Number of subjects included by the Dermatologist Investigator 110
Number of subjects discontinued from the study 3
Number of subjects for the analysis of the results
for the evaluation of Primary Cutaneous Irritation
.
no
for the evaluation of Cumulative Irritation
.
108
for the evaluation of Cutaneous Sensitisation
.
107
The physical characteristics of the subjects are summarized in the following table:
. Primary Cutaneous Cumulative Cutaneous

Subjects .
I rn tafl on I ni tat ion S ens It I san on

Number 110 108 107
Females 97 96 36
Males 13 12 Il
Age minimum (y.o.) 20 20 20
[ Age maximum (y.o.) 69 69 69
RESULTS
Percentage of subjects having presented with one or

several well visible to severe irritation reactions (score 0%
2 during the induction
Mean Irritation Index (Ml].) of the induction 0. Cl
Classification of the investigational product • non-irritant: M.l.l. <0.25
a slightly irritant: Pvl.lI, [0. 25— 7
o moderately irritant: M.I.t. [I -2
o very irritant: Ml.!. [2-3
o__severely_irritant:_MEl._[3—_4[
Percentage of the sensitisation reactions observed 0%
Reactions considered as serious adverse events
0%
linked to the investigational product
Report No B 10031 ORD7- Version I

Page 11/60
CONCLUSION
In conclusion and given the results obtained under the experimental conditions adopted, the single
and repeated epicutaneous applications of tbe investigational product designated as
“MENTHA PIPERITA (PEPPERMINT) LEAF WATER 20% Face Cream batch n NCFI du -
12/jan/2010)”, under occlusive patch, in the healthy adnlt subject, did not provoke any
primary or cumulative irritation reaction, nor any cutaneous sensitization.
Lyon and Sofia,
N.RENTERO E. ATANASSOVA Dr. Z. Panova, M.D.

Ph. D. in Physiology, Engineer in Biotechnology, Dermatologist Investigator
Industrial and Agribusiness Master in Biotechnology
Biochemistry Engineer Deputy Technical and
Responsible for the Study Scientific Manager
This study was conducted by INSTITUT DIEXPERTISECLINIQUE- BULGARIE,

registered by the Bulgarian l-Iealth Authorities
Professor Rumyana YANKOVA, MD., Ph. D., I-lead of the Dermatology
and Allergology Department of Plovdiv Medical University
ReportN 8100310RD7-Veision I Page 17/60
QUALITY CONTROL
This study was conducted in conformity with the Standard Operating Procedures of the Clinical
Research Centre, the signed protocols and ‘in the spirit” of the general principles of the Good Clinical
Practices (ICH topic E 6- CPMP/ICH/135/95).
The quality control of the clinical studies is carried out periodically. It is designed to ensure that all
critical phases (investigational product applications and examinations or measurements) of a particular
study type are controlled, at least once quarterly, for the studies carried out during this time period.
Types and dates of quality controls are given below. When the quality control of a critical phase has
been conducted on another study (of the same type) than the study concerned by the present report, the
sentence “on identical study” is added to the ‘Type of quality control”
The results of these quality controls were reported to the Investigator, to the Dermatologist and to the
General Management.
Type of quality control Dates of quality Dates of reports to Dates of reports to the
controls the Dermatologist General Management
Investigator
. Critical phase(s) 8 April2010 9 April2010 15 April2010

(on identical study)
. Raw data: Induction 21 April 2010 22 April 2010 28 April 2010
. Raw data: Challenge II May 2010 12 May 2010 18 May 2010
This report has been controlled by I.E.C. Bulgarie and 1.E,C. France Quality Units. It constitutes an
accurate and complete reflection of the raw data generated in this study.
Date of quality control Dates of reports to Date of report to the

the Dehmatologist General Management
Investigator
Report
(vs. compiled data): 7 June 2010 7June20 10 7 June 2010
Signature:
28106/ID
Anrelie CHAMBERAUD
Deputy Quality Executive Manager
PEMTESCWa
Cenlrft tie Rechsahe BIomdIcaLe
a -
REPORT
Version 1 (09 May 2008)
OCULAR AND CUTANEOUS ACCEPTABILITY STUDY OF A

CLEANSING GEL DURING 4 WEEKS UNDER OPHTHALMOLOGICAL
AND DERMATOLOGICAL CONTROL
SPONSOR INVESTIGATOR
ADDRESS
PERITESCO
4, rue Villedo
75001 PARIS
STAFF IN CHARGE WITH THIS STUDY
Director and main investigator:

Dr M. PERICOI
Ophthalmologist
Co-investigators:
Dr S. LAQUIEZE
Dermatologist
DrM. RAFAA
Dermatologist
REFERENCES
DT026342
4717-43-ODI
MENTHA
PIPERITA (PEPPERMINT) LEAF
WATER 50% Cleansing Gel
LOT Ll7492694 DU 10/12/2007
Document consisting of97 pages
PE RITES CO —082505 1565

4, rue Villedo Fax: 01 53 2997 25
7500! PARIS R.C.S. Paris B 389 377 672
I out of 42
REPORT DEVELOPMENT
Dr. M. PERICOI: Main Invesligator

Ophthalmologist
D.E.A of Dermopharmacy
Clinical Toxicology and Pharmacology Degree
Clinical Expert (Decree of the 29th ofJune 1985)
Dr. S. LAQUIEZE: Co-Investigator

Dermatologist
Expert in Phase I, II and Ill clinical studies in
Dermatology and Cosmetology
Clinical Expert (Decree of the 29th oJune 1985)
Dr. M. RAFAA: Co-Investigator

Dermatologist
Mrs. A, LADURELLE: Study Director
Mrs. K. LOCH: Assistant

Report Writing
Mr. S. LOURDEZ: Data Control Manager
Mrs. S. ICKOVA Statistical analysis manager
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09 May 2008 2 out of 42
TABLE OF CONTENT
METHODOLOGY 7
I. STUDY DESCRIPTION 7
1.1. ThMSIIO’CTIO4N.J1n CF 7
1.2 GJNOLN’EI1 0J 7
l.2.1.:lii;ioJihe study 7
1.2.2. Relevanci’ 7
1.2.3. Stew/v design 8
1.2.4. Statistics 8
1.2.5. Subjects parlicipating in the stndj 8
1.2,5.1. Inclusion criteria x
1.2,5.2, Non inclusion criteria 9
1.2.5.3. Study premature withdraw a’ criteria 9
1.3. PR&IOCOLANILNDNILN 9
1.4. PROTOCOL DEVIATIONS 9
II. STUDY SCIIEDULE ID

11.1. INYIIAIJIIM: 10
11.2. liNLTItvE 11
III. INVESTIGATIONAL PRODUCT APPLICATION - 12
IV. EThICAL AND JURIDICAL CONSIDERATIONS .. 13

IV.I. Iflhl 13
IV.2, CCNXII(ThS1003PAINIl ItSUIItC’IS IM’aMDca’sRqIs 13
IV.3. INt4JR’v’U 13
IV.4 . Sht.flY IIUNC 13
IV.5. Cxyslii[fl.1IAUIY 14
IV.6. QJALflYIOUfl’ 14
IV.7. cU.iJ1YCDNwDI 14
OPIITIIALNIOLOGICAL RESULTS IS
V. SUBJECTS OCULAR CHARACTERISTICS IS
VI. CLINICAL RESULTS 15

VII. It’CflO’ALSISNS 15
VI.2. l1ftS1cALSIG 18
VII. TEAR FILM BREAK-UP TIME MEASUREMENTS 21
VIII. COLORIMETRIC EXAMINATION OF CORNEAAND CONJUNCTIVA 22
DERMATOLOGICAL RESULTS 27
IX. SUBJECTS CUTANEOUS CHARACTERISTICS 27
X. CLINICAL RESULTS 27
X. I. FLJNCTIONALSIGNS 27
X.2. PHYSICAL SIGNS 29
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09 May 2008 3 out of42
XI. COSMETIC ACCEPTABILITY OF THE INVESTIGATIONAL PRODUCT 32
XII. INVESTIGATIONAL PRODUCT WEIGHING 32
XIII. UNEXPECTED EVENT 32
DISCUSSION- CONCLUSION 33
XIV. SUBJECTS CIIAILACFERISTICS 33
XV. DISCUSSION 33
XV.l. OCULAR ACCEPTABILIIY OF1 HE INVESt IGAlIONAL PRODUC 33
(a) Functional signs investigation and Co lilac t rate 33
(h) Physical signs 33
(c) A dditional ocular exam inalions 34
(i) Tear fllm break—up time meastirement 34 (ii)
Colorimetric exam mat ion of cornea and coilj unctiva 31 (iii)
Contact lenses examination 34
(d) Results summary 34
XV.2. INVESTIGATIONAL PRODUCT COMPARISON 35
XV.3. CUTANEOUS ACCEPTABILITY OF TIlE INVESTIGATIONAL PRODUCT 36
I) Salety 37
(a) F tinclional signs 37
(b) Physical signs 37
(c) Comments 17
(d) Conclusion 38
2) Comfort 3%
(a) Functional signs 3%
(h) Physical signs 3%
(c) Comments 38
(d) Conclusion 39
XV.4. COSMETIC ACCEPTABILITY OF THE INVFSTIGATIONAI., PRODUCT 39
XVI. CONCLUSION 41
XVII. SIGNATURES 11
APPENDIXES 32
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CERTIFICATE OF QUALITY POLICY
TITLE: OCULAR AND CUTANEOUS ACCEPTABILITY STUDY OF A CLEANSING

GEL DURING 4 WEEKS UNDER OPHTHALMOLOGICAL AND DERMATOLOGICAL
CONTROL
REFERENCES: 4717-43-ODI
DT026342
INVESTIGATIONAL PRODUCT: MENTHA PIPERITA

(PEPPERMINT) LEAF WATER 50% Cleansing Gel LOT L17492694
DU 10/12/2007
MAIN IN VESTIGATOR: Dr M. PERICOI.
To my knowledge, the study described in this report was carried out according to the
protocol, to PERITESO Standard Operating Procedures and to the standards of the
Good Clinical Practice Guidelines according to the guidelines of the International
Conference on Harmonization (ICl-l Topic E6 <<Note for guidance on Good Clinical
Practice CPMP/ ICH! 135/ 95), the FDA (62 FR 25692 of May 9. 1997). and the EEC
(Directive n° 2001/20/CE ofApril4, 2001).
The following table mentions the audits that were carried out during the study, and the
date of transmission of the audits reports to the investigator and the study director:
Type of audit Date

Protocol audit 22/01 12008
Preliminary results audit 06/03/2008
Report audit 02/05/2008
This report only contains the results of the ocular, cutaneous and cosmetic acceptability of
the investigational product. Those of its subjective efficacy are the aim of another report.
No event affecting the quality or integrity of the data occurred.

P. 0. A. DAH MACHE
WI
/Mis M. H)RING
date
Quality Policy
PER ITESCO
4717-43-ODI Rapp Tol+Ace cosrnvl

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CERTIFICATE OF QUALITY CONTROL
TITLE: OCULAR AND CUTANEOUS ACCEPTABILITY STUDY OF A CLEANSING

GEL DURING 4 WEEKS UNDER OPHTHALMOLOGICAL AND DERMATOLOGICAL
CONTROL
REFERENCES: 4717-43-ODI
DT026342
INVESTIGATIONAL PRODUCT: MENTHA PIPERITA

(PEPPERMINT) LEAF WATER 50% Cleansing Gel LOT L17492694
DU 10/12/2007
MAIN INVESTIGATOR: Dr M, PERICOI.
A quality control program checked that the report presents the raw data of the study.
All the controls on the data veracity and conformity with the protocol were performed at
each step of the study:
Controls Date Controlled by

Protocol Conformity 16/01/2008 AL
Case Report Form 23/01/2008 AL
Clinical Data 28/02/2008 SL
Questionnaire 03/03/2008 AL
First Results 03/03/2008 AL
Report 29/04i2008 AD
09/1)5/2 008
‘krs A. LADURELLE date
Quality Control
PERITESCO
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09 May 2008 6 out of 42
METHODOLOGY
1. STUDY I)ESCRIPTION.
1.1. Investigational product.
The investigational product was supplied by
This investigational product had the following characteristics:
Investigational product MENTHA PIPERITA

denomination (PEPPERMINT) LEAF WATER 50% Cleansing Gel lot
Ll7492694 du
10/12/2007
Presentation Liquid gel
Packaging Plastic tube
Quantity supplied 55 samples
Date ofreceipt 08 January 2008
Storage Between 15CC and 25CC.
1.2. Clinical en ethods.
I .2.1. Aim of the study
This study, carried out on cosmetic products whose security was previously assessed by a
toxicologist, was perlbrmed in order to confirm the safety of these products which will be
used by a large amount of users, in normal and reasonably foreseeable conditions of use.
The aim of the study was to confirm the ocular. pen-ocular and cutaneous acceptability of
the investigational product as well as its cosmetic acceptability in the normal conditions
of use. as foreseen by the sponsor, under ophthalmological and dermatological control.
1 .2.2. Relevancy
Cosmetic products can induce ocular, cutaneous or mucous discomfort and/or irritation
signs.
The medical ophthalmologic and demiatological supervision ofa group of subjects using a
cosmetic product in nonnal conditions of use, the collection of the functional signs and the
observation of the physical signs that appeared during the period, as well as the analysis
of the investigational product imputability. allow to evaluate the investigational product
security, its ocular, pen-ocular and cutaneous acceptability and to classify its irritant
potential.
The analysis of the standard deviation of each studied sign allowed to determine the
number of subjects to include in the study. The occurrence frequency standard deviations
as well as physiological criteria allowed to determine the duration of the study.
The number of subjects. the frequency of use and the duration of this study are
satisfactory to study ocular, pen-ocular and cutaneous acceptability of the investigational
product.
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(V Nty 2008 7 out of42
The investigational product was apphed on the face and the neck, which corresponds to
the usual use of this kind of product.
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1.2.3. Study design

*
Location: The study was carried out at the clinical unit of Paris.
*
Desiun: The study was open and non-randomized.
*
Timetable: - Clinical study start date: 24 January’ 2008
- Clinical study end date: 22 February’ 2008
1.2.4. Statistics
The statistical analysis sas carried out in accordance with the statistical protocol
included in the study protocol (See procedures in Appendix I).
1.2.5. Subjects participating in the study
The following table gives information about the participation in the study of all the
retained subjects:
Number of
subjects Reason and day of occurrence
Recruited 52
Non-Included 0
. Subjects n° 6 and 42: lost to follow-up at
Study premature withdrawals 2
Final Time
Not analyzed data 0
Valid cases 50
The study was performed in three groups of sub jects:

Group 1: 20 subjects with sensitive eyes,
Group 2: II subjects with non—sensitive eyes,
Group 3: 19 subjects wearing contact lenses.
The average age of the subjects was:

Average age: 39.9 ± 11.6 years old (extreme values: 20- 63 years old).
The subjects were selected according to the following criteria:
1.2.5.1. inclusion Criteria

Were included the subjects:
Voluntary,
Fern ale,
Being over 18 years old,
Presenting a combination to oily skin among which at least 50% of sensitive skin.
At least 20 subjects with sensitive eyes according to the following criteria:
o tear film break-tip time inferior to 10 seconds.
o and/or lid margin examination revealing a seborrheic hypersecretion with
at least a slight intensity and/or a dysfunction or an atrophy of
ineiborn ius glands.
o and/or subjects fulfilling the subjective criteria of organic ocular
sensitivity without optical ocular sensitivity (photophobia. astigin atisrn
heterophoria, cataract or corneal scars).
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At least ID subjects with non-sensitive eyes according the following criteria; who
did not fulrill the sensitive eye criteria described above,
At least 20 contact lenses wearers, traditional soft lenses, disposable or with a
month replacement or flexible. (For the lenses with a month replacement, the
subjects did not change their lenses during the study),
Able to give their written participation consent,
Affiliated to the social security in accordance to the recommendations of the
French law (“Lol Huriet’; n° 68.1138- 20.12.88) abotit the biomedical research.
1.2.5. 2MlIrdwb7Oft&a
Were not included the subjects;
Taking part or willing to take part of another study during the study period,
Who could not commit themselves on the absence of pregnancy or breastfeeding
during the study period,
Presenting a medical history of medical or psychiatric illness or major surgery,
suffering from acute or chronic or progressive illnesses, or presenting a
dermatological and/or ophthalmological pathology likely to interfere with the data
of the study.
Unwilling to give their written informed consent.
Who could not be contacted in case of emergency by phone.
PERITESCO’s staff members.
Who did not fulfill the inclusion criteria.
1.2.5.3. t4’penthn wYdmU Oit&a

A subject included in the study was excluded if;
The investigator judged that an unexpected event was directly attributable to the
investigational product,
A hypersensitive reaction or an allergic reaction directly linked to the
investigational product occurred,
If the subject wanted to withdraw from the sttidy. whatever the reason,
In case the subject did not respect the study constraints.
In case of no adequacy during the study with the initially checked inclusion
criteria,
Lost to follow-up subect.
1.3. Protocol amendment.
One amendment was requested by the sponsor and is mentioned in the following table;
TYPE OF MODIFICATION DATE

Addition of Dr M. RAFAA as investigator 31 January 2008
The protocol amendment is presented in Appendix II.
1.1. Protocol deviations.
The study was conducted according to the protocol specifications.
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However, the following deviations were observed:
Type ol deylaHon
‘‘%
S tti dv Number of
SubjectTh%. Number of Type of . Missing
Age . duration applications
subjects subjects examination
26<29<32 51<57<63
19 subjects
Contact lenses
instead of at
wearers panel
least 20
Percentage of
. 44% subjects
subjects
. instead of at
having a
. least 50%
sensitive skin
Subject no 26 49 applications
Subject no 8 46 applications
These deviations had no consequence on the validity oftlie observed results.
H. STUDY SCHEDULE.
11.1. Initial Time.
The subjects received a daily-log where they daily recorded the use of the investigational
product and the possible signs felt or observed during the use, or any other information.
* . .
TO: before application of the investigational product.
The ophthalmologist practiced:

A functional signs investigation on both eyes (Groups I, 2 and 3),
A biomicroscopic examination of ocular and pen-ocular structures on both eyes
(Groups I, 2 and 3),
A colorimetric examination of the cornea and the conjunctiva on right eye
(Groups I and 2),
A tear film break-up time measurement on right eve (Groups I and 2),
A contact lenses exam nation on both eyes (Group 3).
The dermatologist practiced:

A cutaneous functional signs investigation (Groups 1. 2 and 3),
A dermatological examination of the face and the neck with search of physical
signs (Groups 1, 2 and 3).
*TIo mm: at least 10 minutes after application of the investigational product.
The ophthalmologist practiced:

A functional signs investigation on both eyes (Groups 1, 2 and 3),
A biomicroscopic examination of ocular and pen-ocular structures on both eyes
A colorimetric examination of the cornea and the conjunctiva on right eye
(Groups I and 2),
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W N’hy 2008 Ii out of42
A tear film break-up time measurement on right eye (Groups I and 2),
A contact lenses examination on both eyes (Group 3).
Every observation was reported in the case report form.
11.2. Final Time.
The subjects answered a cosmetic acceptability questionnaire about the investigational

product (Groups I, 2 and 3).
*TO: before the last application of thc invcstigational product.
The dermatologist practiced:

A cutaneous functional signs investigation analyzing the observations recorded
in the daily-log (Groups I, 2 and 3),
A dermatological examination of the lace and the neck with search of physical
signs (Groups I, 2 and 3).
*
Tb m in: at least 10 minutes after the last application of the investigational
product.
The ophthalmologist practiced;

A functional signs investigation on both eyes analyzing the observations
recorded in the daily-log (Groups 1, 2 and 3).
A biom icroscopic examination of ocular and pen-ocular structures on both eyes
A colorimetnic examination of the cornea and the conjunctiva on right eye
(Groups I and 2),
A contact lenses examination on both eyes (Group 3).
Every observation was reported in the case report form.
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III. INVESTIGATIONAL PRODUCT APPLICATION.
During the study, the investigational product was used as follows:
Application area The face and the neck

Applied quantity Necessary and sufficient for this kind of product
Frequency Twice a day
Duration 4 weeks
Total number ol
applications on the 2793 applications
whole panel
The investigational product was applied on the face and the
neck, twice a day, in the morning and in the evening, during
four weeks.
The first and the last applications were performed at the

. . clinical unit.
Conditions of use
Direction for use
Moisten hands, race and neck.
Apply on the face and the neck. Make the investigational
product foam by massage in circular motions.
Rinse thoroughly.
Allowed: (except when coming to the clinical unit for the
control visits)
-Usual face and lip make-up remover, in the evening, if
necessary (to be used before the application of the cleansing
gel),
-Usual care products.
Study constraints -Light face make-up (powder and blush) and lip make-up
with usual prod ucts.
Not allowed:
- Any olher face and neck cleanser.
- Any eyes in ake-up.
- Any modification of the other cosmetic hab its.
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09 May 200% 12 out of42
IV. ETHICAL AND JURIDICAL CONSIDERATIONS.
WI. Ethics.
The stud’, without an’ direct therapeutic aim. was carried out according to the most
recent recoin inendations of the World Medical Association (Helsinki Declaration of 1964,
and its successive updates). As this study is not concerned with the French law nC 88-1138
of December 20, 1988 about the protection of subjects involved in biomedical research, and
its successive updates. the last one being the law n° 2004-806 of August 9, 2001, the CPP
authorization was not required. However, the principles of this law were respected, except
the recording of the subjects in a national file and the submission of the documents
related to the study to an Independent Ethics Committee.
The investigational product did not contain and was not derived from in aterial with
specific risks as defined by the Commission decision n° 2000/418/CE, modified by the
Commission decision nD2001 12/CE.
IV.2. Conditions to obtain the subjects’ informed consents
On the inclusion day, the investigator or the person delegated by the investigator
provided to the subject a detailed information about the study modalities so that the
subject could decide whether or not he or she wants to participate in the study. The
investigator or the person delegated by the investigator made sure that the subject
obtained answers to all the questions he or she asked concerning his or her participation
in the study.
Two copies of the informed consent were signed and dated by the subject and then
checked, countersigned and dated by the investigator or the person delegated by the
investigator.
IV.3. Insurance.
The study was covered by the insurance contract subscribed by the sponsor, civil liability
contract covering the studies on healthy subjects, by AIG Europe, contract n° 7.109.393.
Moreover, the investigator subscribed a civil liability insurance by AGF, contract n° 41

263 662.
WA. Study filing.
The investigator retains a copy of the protocol and its possible amendments, the financial
agreement. signed by the sponsor and himself, of all the versions of the reports, the
original case report forms and everything that was used to fill them in, the informed
consent fonns, the source documents and all the documents concerning the study for a
period of ten years after the completion of the study. The whole of the computerized data
of the study will be stored on an internal network for 10 years as well.
In accordance with PERITESCO SOP, the paper documents archiving is outsourced in

Societe Generale d’Archives. The traceability of the documents will be the responsibility of
PERITESCO. who will keep updated records of their filing address. These documents will
be available for inspection within a reasonable period by an authorized sponsor
representative or by the regulatory authorities.
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All the investigational products (including the investigational products given back by the
subjects at the end of the study and the possible investigational products in surplus) are
destructed by the investigator two weeks after sending the first results to the sponsor.
unless otherwise indicated by the sponsor or the investigator in the beginning of the study
or according to the results.
A sample of the investigational product is stored in the clinical unit where the study took
place. for 6 months after sending of the study report. according to the PERITESCO SOP.
IV.5. Confidentiality.
The investigator grants the study sponsor for data monitoring or audit, the regulation
authorities, as well as the ethical committee if need be, permission to have direct access to
study source documents without violation of data confidentiality.
The confidentiality of the personal data of the subjects participating to this study was
maintained all the study long, in accordance with the law “lnformatique et libene” of
January, 6th 1978 and with the Helsinki Declaration. To ensure their anonymity, a five-
letter code was attributed to each subject. This code was made of the first three letters of
their surname folloed by the first two letters of their first name.
The results of this study are considered as confidential information.

This information, or any part of it. will not be disclosed, submitted for common
publication or be the object of industrial property. unless the sponsor agreement is
obtained.
The results gained through this study will remain the property ofthe sponsor.
Neither publication nor communication could be made without the previous agreement of
the sponsor of the study.
IV.6. Quality policy.
This study was conducted according to the protocol. the standard operating procedures
and to the standards of the Good Clinical Practice Guidelines according to the
International Conference on Flarmonization (ICR Topic E6 Note for guidance on Good
Clinical Practice CPMP/ ICH/ 135/ 95 >>), the FDA (62 FR 25692 of May 9. 1997). and the
EEC (Directive no 2001 120/CE of April 4.2001).
A quality policy statement mentioning the audits carried out during the study is included
in this report.
IV.7. Quality control
The protocol. the case report Forms, the preliminary results and the reports are
systematically submitted to quality control in order to verify that they are correctly
written, complete and coherent. These controls are performed and registered all the study
long and are the object ofa statement in this report.
All the raw data of the study (whether captured on paper or computerized) were
submitted to quality control. The date and identification of the person who performed the
control of the data are registered.
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09 Miy 2008 14 out of42
OPUTHALMOLOGICAL RESULTS
V. SUBJECTS OCULAR CHARACTERISTICS.
The following table presents the subjects ocular characteristics:
Characteristics Percentage of subjects

Sensitive eyes 40.0
Ocularcriteria Non sensitive eyes 22.0
Contact lenses wearers 38.0
The subjects individual characteristics are presented in Appendix IV.
VI. CLINICAL RESULTS.
Vl.l. Functional signs.
No subject showed any functional sign at Initial Time TObefore the first application of the
investigational product.
The following tables present the functional signs which appeared during the study in the
different groups:
*
Sensitive eyes panel:
- Number of %of Frequency Grade Grade Grade

occurrences subjects I 2 3
Ocular stinging 0 0.00 0.00 0 0 0
Ocularburning 0 0.00 0.00 0 0 0
Foreign body
0 0.00 0.00 0 0 0
feeling
Blur 0 0.00 0.00 0 0 0
Palpebral stinging
0 0.00 0.00 0 0 0
or burning
Other sign 0 0.00 0.00 0 0 0
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*Non_sensitive eyes panel:
Number of %of Frequency Grade Grade Grade

occurrences subjects I 2 3
Ocular burning 0 0.00 0.00 0 0 0
Foreign body
0 0.00 0.00 0 0 0
feeling
Blur 0 0.00 0.00 0 0 0
Palpebral stinging
0 0.00 0.00 0 0 0
or burning
Other sign 0 0.00 0.00 0 0 0
‘
Contact lenses wearers panel:
Number of %of Frequency Grade Grade Grade

occurrences subjects ID 1 2 3
Ocular burning 0 0.00 0.00 0 0 0
Foreign body 0
0 0.00 0.00 0 0
feeling
Blur 0 0.00 0.00 0 0 0
Palpebral stinging
0 0.00 0.00 0 0 0
or burning
Other sign 0 0.00 0.00 0 0 0
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*WhoIe panel:
Nb Total
%of Freq. Average Cr Or Or Delay Duration Irritant
of 0/
irritation
su bject s o intensity I 2 3 mm mm Freq.%
0CC frequency
Ocular
0 0.00 c.o o 0.00 0.00 0.00
stinging — -
OMO
Ocular 0.00 0.00 0.00
0 0.00 0.00 0.00 0 0 0
burning
Foreign
. 0 0.00 0.00 0.00 0 0 0 0.00 0.00
body feeling
Blur 0 0.00 0.00 0.00 0 0 0 0.00 0.00
Palpebral
stinging or 0 0.00 0.00 0.00 0 0 0 0.00 0.00
burning
Other sign 0 0.00 0.00 0.00 0 0 0 0.00 0.00
Key: Nb ofocc Number of occurrences

Freq Frequency
Cr Grade
Mm Minutes
The ocular irritation occurrences regroup the following functional signs: ocular stinging
and burning with an intensity and/or duration meaning an irritation.
The objective contact rate noticed by the investigator is 0.00% (of the applications).
The individual data are presented in Appendix V.
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09 May 2008 17 out of 42
VU. Physical signs.
The following table presents the physical signs which appeared during the study:
INITIAL TIME TO INITIAL TIME Tb mm
Average Number of Average Number of — Bilateral

grade occurrences grade occurrences I occurrences
CU
t_
(I
‘.
fr
‘—
C
Seborrheic right 0.40 20
hypersecretion left 0.40 20 — — —
Dysftmnction of glfl 0.00 0

meibornius
glands left 0.00 0 — — —
iEbi 0.00 non .ix n_._o

Eyelids 0
left 0.00 0 0.00 0 0 0 0
Bulbar right 0.00 0 0.00 0 S 0 0
conjunctival 0
redness left 0.00 0 0.00 0 0 0 0
Conjunctival right 0.00 0 —
pallor left 0.00 0

jg]it non p
Papillae
left 0.00 0
jgt non I
Folliculosis I
left 0.00 0

09 May 2008 18 out of42
FINAL TIME T1O m in

Average Number of Grade Grade Grade Bilateral
grade occurrences I 3 occurrences
Seborrheic [UZI 0.40 -

20. ._O 0.
hypersecretion left 0.40 20 20 0 0 —
Dysftinctionof right 0.00 0 9 0 0

meibornius 0
glands left 0.00 0 0 0 0
. ..rght. 0. 0
Eyelids 0
left 0O0 0 0 0 0
Bulbar right 9 9 0
conjunctival 0
redness left 0.00 0 0 0 0
Conjunctival right 0.00 0 0 0 0

0
pallor --jj: 0.00 0 — 0
. right_0.Q0 ._.......JJ_____ 0... -
Papillae 0
left 0.00 0 0 0 0
right . 0.00 0 . 0 - 0. . 0.
.
Folliculosis 0
left 0.00 0 0 0 0
The folloing table presents the number of subjects Wio shoed corneal cells loss.
Total number of Surface Depth

Number
corneal cells loss (Grade from 0 to 10) (Grade from 0 to 3)
Initial Tin-e TO 0
Initial Tine Tb mm 0
Final Tine Tb mm 0
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09 May 2008 19 out o142
If
The following tables present the physical signs observed during the study.
* Initial Time TO
No Seborrheic hypersecretion
CODE Type
(Grade)
I MELPA s I
2GELAN s I
3 BRUAL s
4NAMVE s
5 BRAFR s
7 01-IRMA s 1
8 GADIS s
9 BENKE s I
IC WANBR s
11 SCHNI s I
12 FOUMU s I
13 PFEMA s I
14BAZNO s I
15 LAIRA s I
I6YAHSO s I
17 DRASA s
ISDUFBR S
19130UN0 s I
33 CATVI s I
21 CALLI s 1
Key: s: Subjects with sensitive eyes
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09 May 2008 20 out of 42
*Final Tint TIOmin
Seborrheichypeisecitt ion
Type
MELFA
2 GELAN s
3 BRUAL s I
NAIvIVE s
5 BRAFR s
7 GHEMA s
8 GACIS s
9 BENKE s
10 WANBR s 1
SCHNI S
12 FOUM1J s
13 PFEMA s
jj BAZNO s I
15 LAIRA s
I6YAHSO s I
17 DRASA s
I8DUFBR s
I9BOUNO s I
20 CAT’)! s I
¶[ CALLI s I
Key: s: Subjects with sensitive e’ Cs
VII. TEAR FILM BREAK-UP TIME MEASUREMENTS.
The comparison between individual levels of break-up times before and after application
was carried out using a match paired Wilcoxon test (signiflcativity threshold= 5%).
The following table presents the results:
BUT. values (seconds) Statistics
Initial Time Initial Time Initial Time 101 Initial

Difference
lint T10 mm
T10 miii
Sensitive eyes
6.35 ± 1.76 5.45 ± 1.61 p = 0.047 Significant
panel
Non-sensitive
9.82 ± 2.44 8.82 ± 1.78 p = 0.072 Not significant
eyes panel
Whole panel 7.58 ± 2.60 6.65 ± 2.32 p = 0.007 Significant
The individual data of the break-up time measurements are presented in Appendix V.
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09 May 2008 21 out of 42
viii. COLORIMETRIC EXAMINATION OF CORNEA AND

CONJUNCTIVA.
The following tables present the colorimetric indexes obtained at dirferent times:
*
Sensitive eyes panel.
*lnitialTinle TO.
Surface
Superior Inferior
Superior cornea Inferior cornea
c 0 nj u n c t i v a Co nj U fl c t iv a
Number of subjects with
0 0 0 0
a grade different from 0
Rate(%) 0.00% 0,00% 0.00% 0.00%
Average conjunctival
0.0 00/
rate(%)
Average corneal rate(%) 0.00%
. Depth

0 0
Depth 0.00 0.00
Average depth 0.00
‘ Initial Time TI0 mm.
. Surface
Superior Inferior
. . . . Superior cornea Inferior cornea
conjunctiva conjunctiva
Number of subjects with 0
0 0 0
aate(%) 0.00% 0.00% 0.00% 0.00%
0.00%
rate(%)
Depth

0 0
Depth 0.00 0.00
Average depth 0.00
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09 Miy 2008 22 out of42
*Fina! Tint Tb miii.
Surface
Superior Inferior
Conlunctiva conjunctiva
. 0 0 1 Grade! I Grade!
a giide different from 0
Rate(%) 0.00% 0.00% 0.5O% 0.5O%
Average conjunctival 0.000%
rate( /o)
Average cornea! rate(%) 0.50%
. Depth

. - I Gradei I Grade!
a gth diflbrent 1mm 0
Depth 1.00 1.00
Average depth 1.00
*Non_sensitive eyes panel.
*Initial Time TO.
. Surface
Superior Inferior
. . . Superior cornea Inferior cornea
conjunctiva conpunctiva
0 0 0 0
Rate(%) 0.00% 0.00% 0.00% 0.00%
0 00%
rate(%)
Average corneal rate(%) 000¾
• Depth
Superior cornea inferior cornea

0 0
Depth 0.00 I 0.00
Average depth WOO
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09 Miy 2008 23 out of42
*
Initial Time T10 miii.
Surface
Superior Inferior
0 0 0 0
Rate(%) 0.00% 0.00% 0.00% 0.00%
0 00%
rate(%)
. Depth
Superior_cornea Inferior_cornea
Number of subjects th
0 0
Depth 0.00 0.00
Average depth 0.00
*
Final lime 110mm.
. Surface
Superior Inferior
. . . . Superior cornea Inferior cornea
coni uncti va conjunctiva
0 0 0
Rate(%) 0.00% 0.00% 0.00% 0.00°A
0 00%
rate(%)
Average corneal rate(%) o.oo%
Depth

0 0
Depth 0.00 0.00
Average depth 0.00
4717-43-ODI Rapp To! -I-Ace cosm vI

09 Miy 2008 24 out of42
*wholc panel.
*
Initial Tine it.
Surface
Superior Inferior
0 0 0 0
agrade different fitrn 0
Rate(%) 0.00% 0.00% 0.00% 0.00%
0 00°/
rate(%)
Average conical rate(%) 0.00%
. Depth

0 0
Depth 0.00 0.00
Average depth 0.00
Initial Tint TI0 mm.
. Surface
Superior Inferior
. . . . Supenor cornea Inferior cornea
conlunctlva conjunctiva
0 0 0 0
a grade different fiom 0
Rate(%) 0.00% 0.00% 0.00% 0.00%
0 00%
rate(%)
Average cornea! rate(%) 0.00%
Depth
Superior cornea I Inferior cornea

0 0
Depth 0.00 0.00
Average depth 0.00
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0’) Miy 200% 25 out of42
*Final Tint TI0 miii.
Surface
Superior Interior
SupeHor cornea Inferior cornea
0 0 I Gradel I Gradel
Rate(%) 0.000/n 0.00% 0.32% 0.3r/0
0.00%
ratc(%)
• Depth
Superior cornea I inferior cornea

I Gradel I Gradel
a urade different lInt 0
Depth 1.00
I 1.00
Average depth I .00
* Results of colorimetric gloI indexes of the investigational product

(maximal values between the difference between the colorimetdc index
Initial Tint 110 nm and Initial Tine lOaixI between fir difference
between the colorirnetric index Final lint 110 am and Initial Time
1O
Results
I Maximal coniunctival index 0.00%
I Maximal corneal index 0.32%
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) May 2008 26 out of42
DERMATOLOGICAL RESULTS
IX. SUBJECTS CUTANEOUS CHARACTERISTICS.
The following table presents the subjects cutaneous characteristics:

. Sensitive skin 44.0
Skin type -
Non-sensitive skin 6.O

. Oily skin 2.0
Skin nature
Combination skin 98.0
The subject’s individual characteristics are presented in Appendix IV.
X. CLINICAL RESULTS.
X.l, Functional signs.
The following tables present the functional signs observed during the study:
*
Initial Time TO:
Number of %of Average Grade Grade Grade Grade

occurrences subjects intensity 1 2 3 4
Cutaneous
0 0.0 0,00 0 0 0 0
stinging
Pruritus 0 0.0 0.00 0 0 0 0
Burning 0
0 o.o 0.00 0 0 0
feeling
Discomfort 2 0 1 0
3
“ 6.0 1.67
feeling
Tugging 2
10 20.0 1.60 6 2 0
feeling

W May 2008 27 out of42
*Final Tint ‘Ifl
Number of %of Freq Average Grade Grade Grade Grade Duration

occurrences subjects .% intensity I 2 3 4 grade
Cutaneous 2.00
2 4.0 0.18 0 2 0 0 1.4
stinging
Pruritus 0 0.0 0.00 0.00 0 0 0 0 0.0
Burning
0 0.0 0.00 0.00 0 0 0 0 0.0
feeling
Discomfort
0 0.0 0.00 0.00 0 0 0 0
feeling
Tugging
5 10.0 3.35 1.80 2 2 I 0
feeling
Key: Freq:Frequency
The following tables present the subjects who presented functional signs during the study:
* Initial Time T!
Discomfort Tugging
No CODE Type Nature
- feeling (Grade) feeling (Grade)
4NAMVE n M 0
SGADIS n G 0
IS LAIRA s M 0
22VALMA n M 3 0
23 SCHVE 5 M 1 0
27BERBR n M 0
3IJARED s Ni 0 I
33ANDFL n M 0 3
36MAHMA n M 0 2
44DALAL s M 0 3
49AUZCH s M 1 0
5OSAUED s M 0 2
52BERDA n M 0
Key: s: subjects with sensitive skin

n: subjects with non sensitive skin
M: combination skin
G: nily skin
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09 May 2008 28 out nC42
*Final Tint TO
Cutaneous stinging Tugging feeling

1b Type
CODE Nature Grade Number Grade Number
n M 0 E 0 3 54
8GADIS n G 0 0 2 15
I4BAZNO15 M 0 0 I I
15 LAIRA s M 0 0 2 15
24ROUCR s M 0 0 I 7
44DALAL s M 2 4 0 0
48BIACE[s M 2 I 0 0

n: suhjccLs with non sensitive skin
M: corn hination skin
G: cliv skin
The individual data are presented in Appendix VI.
X.2. Physical signs.
The following tables present the physical signs observed during the study:
*lnitial TimeTO:

occurrences subjects intensity I 2 3 4
Erythema 29 58.0 1.24 22 7 0 0
Dryness 8 16.0 1.63 3 5 0 0
Roughness 3 6.0 1.00 3 0 0 0
Desquamation 6 12.0 1.17 5 I 0 0
Final Time TO:

occurrences subjects intensity I 2 3 4
Erythema 22 44.0 1.23 18 3 I 0
Dryness 9 18.0 1.11 8 I 0 0
Roughness I 2.0 1.00 I 0 0 0
Desquarnation 3 6.0 1.00 3 0 0 0
-V
471 7-13-001 R2ipp Tel ±Ace cosm vi
09 May 2008 — 29 out o142
The following tables present the subjects who presented physical signs during the study:
*lnitialTiite TO
Ervthema Dryness Roughness Desquamation

No Code Type Nature
(Grade) (Grade) (Grade) (Grade)
I MELPA n NI () 2 0 0
2 GELAN s M I 0 0 0
3BRUAL s NI I 0 0 0
5I3RAFR n M 0 I 0 0
7GHEMA s M 2 0 0 0
8 GADIS n G 0 2 0 I
9flENKE n M I 0 0 0
I0WANBR s M 2 0 0 0
12 FOUMU n NI I 0 0 0
I4IIAZNO s NI 0 2 0
15 LAIRA s M 2 0 0
I7DRASA n NI I 0 0 I 0
ISDUFHIt n NI I 0 0 0
I9BOUNO n NI I 0 0 0
20 CATV n NI I 0 0 0
22 VALMA n NI I 0 0 0
23 SC[IVE s NI 2 0 0 0
21ROUCR s NI 0 0 0
26SARJA s NI I 0 0 0
27 BERBR n NI I 0 0 0
30 LAMSA s NI 0 0 I 0
3IJARED S NI I 0 0 0
33 ANDFL n NI I 0 0 0
38I30NMA n NI 2 2 0 2
39LEVSA n M 0 I 0 0
4OGILAN n NI I I 0 0
4IAZOCA s NI I 0 0 0
43OMECA s NI I 0 0 0
44DALAL s NI 2 0 0 0
45 LAUCA s NI I 0 0 0
46 KASCI n NI () 2 I 0 1
47TL’PCII s M I 0 I 0 0
48HIACE S NI I 0 I 0
49 AVZCH sJ NI 2 0 0 0
51 MAISU NI I 0 0 0
52BERDA n NI I 0 I 0
53 LEVEL s NI I 0 0 0

n: subjects 1W lion sensitive skin
NI: combination skin
G: oil skin
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09 May 2008 30 out of42
*
Final Yin TO
Erythema Dryness Roughness Desquamation

No Code Type Nature
(Grade) (Grade) (Grade) (Grade)
IMELFA n M 0 I 0 0
2GELAN s M I 0 0 0
3BRUAL s M I 0 0 0
5BRAFR n M 0 I 0 0
7GHEMA s M I 0 0 0
8 GADIS n G 1 0 0 1
IOWANER s M 2 0 0 0
I2FOUMU n M 1 0 0 0
I4BAZNO s M 0 I 0 0
I7DRASA n M I 0 0 0
I8DUFBR n M 1 0 0 0
I9BOUNO n M 1 0 0 0
20 CATVI n M I 0 0 0
22VALMA n M 0 I 0 0
23SCHVE s M 2 0 0 0
26 SARJA s M I 0 0 0
27BERBR n M 1 0 0 0
34SERAN s M 0 I 0 0
3BBONMA n M 2 I 0 0
39LEVSA n M 0 I 0 0
4OGILAN n M I 0 0 0
4IAZOCA s M I 0 0 0
43OMECA s M 0 I 0 0
44 DALAL s M 3 0 0 0
46 KASCI n M 0 2 0 1
47TUPCH s M I 0 0 1
48 BIACE s M I 0 I 0
49 AUZCH s M I 0 0 0
51 MAISU s M 1 0 0 0
S2BERDA n M 1 0 0 0
Key: 5: subjects with sensitive skin

n: subjects with non sensitive skin
M: combination skin
G: oil skin
The individual data are presented in Appendix VI.
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09 May 2008 31 out of42
XI. COSMETIC ACCEPTABILITY OF THE INVESTIGATIONAL

PRODUCT
The following table presents the percentages obtained for each item.
These results also expressed in num her of subjects are calculated in the 50 subjects who
took part in the whole study.
S=Y
AGREE DISAGREE
ZionsE
SENSORY_FEATURES
The color of the product is pleasant 70.0% (35) 24.0% (12) 4,0% (2) 2.0% (I)
The texture ofthep roduct is pleasant 64.0% (32) 32.0% (16) 0.0% (0) 4.0% (2)
The aspect of the product is pleasant 60.0% (30) 34.0% (17) 4.0% (2) 2.0% (1)
The scent of the product is pleasant 46.0% (23) 22.0% (II) 18.0% (9) 14.0% (7)
APPLICATION
The product is easy to apply 76.0% (38) 18.0% (9) 6.0% (3) 0.0% (0)
The application is homogeneous/uniform 82.0% (41) 18.0% (9) 0.0% (0 0.0% (0)
ACCEI’TABILITY
The product is comfortable 52.0% (26) 44.0% (22) 2.0% (1) 2.0% (1)
The product is suitable for me 54.0% (27) 34.0% (17) 6.0% (3) 6.0% (3)
The product is suitable for my skin type 50.0% (25) 34.0% (17) 10.0% (5) 6.0% (3)
The product foams well 68.0% (34) 18.0% (9) 8.0% (4) 6.0% (3)
The product is easily rinsed off 70.0% (35) 24.0% (12) 4.0% (2) 2.0% (I)
APPRECIATION
Globally, the product is pleasant 58.0% (29)1 34.0% (17) I 6.0% (3) I 2.0% (1)
QUESTIONS YES NO
Would you like to continue using the product 74.0% (37) 26.0% (13)
At the end of the test, would you purchase the 42.0% (21)
58.0% (29)
product (regardless oI its price)
MI. INVESTIGATIONAL PRODUCT WEIGHING
The investigational products were weighed before and after a 4-week use.
The average quantity of used investigational product was:
Average quantity of investigational product: 74.2 ± 27.lg (extreme values: 25.7 —
121.2 g). 1.3 g per subject and per application.
The weighing table is presented in Appendix VII.
XIII. UNEXPECTED EVENT.
No unexpected event was reported by the subjects nor observed by the investigator.
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09 May 2008 32 out of42
DISCUSSION- CONCLUSION
XIV. SUBJECTS CHARACTERISTICS.
The following table presents the subjects characteristics:

Sensitive eyes 40.0
Ocularcriteria Non sensitive eyes 22.0
Contact lenses wearers 38.0
Senshive skin 44.0
Skin type . . . -
Non-sensitive skin zO.0

. GUy skin 2.0
Skin nature
Combination skin 98.0
XV. DISCUSSION.
Xvi. Ocular acccptability of the investigational product
(a) Functional skins investigati on and contact rate.
The functional signs are classified in analytical categories. This classification is made
according to the opinion and the experience of the investigator, and according to the
nature of the signs, their intensity, duration and their physiopathology.
The following table presents the appearance frequency of functional signs.
Functional signs Frequency

Ocular irritation functional signs 0.00%
Mechanical ocular functional signs 0.00%
Physico-chemical ocular functional signs 0.00%
Palpebral functional signs 0.00%
The investigational product did not induce the appearance of any ocular and palpebral
functional sign.
The contact rate of the investigational product with the eye is 0.00%, which is very low for
this kind of product.
(b) Ph’sical signs.
The investigational product did not induce the appearance of any ocular physical sign.
which shows an absence of conjunctival and corneal irritant potential.
The investigational product did not induce the appearance of any palpebral physical sign,
which shows an absence of palpebral irritant potential.

09 May 2008 33 out of42
cc) Additional ocular enunmalions.
(i) Tear film break-up time measurement.
The investigational product significantly modifies the tear film stability (the B.U.T. value
decreases from 7.58 to 665).
Probability 0.007 Significant
The investigational product slightly decreases the tear film stability but does
not decrease the ocular surface defense abilities.
(ii) Colorimetric examination of cornea and conjunctiva.
The colorirnetric examinations revealed a maximal corneal index of 0.32% and a maximal
conjunctival index of 0.0O% shich shows an absence of toxicity to the conjunctiva
and a practically nil toxicity to the cornea.
(Hi) Contact lenses examination.
The investigational product did not alter the contact lenses and did not induce any
pathology specific to contact lenses wearers (desit index: 0%).
I’d) Results SYIFFI in an’.
The clinical examinations revealed for this investigational product an ocular irritation
rate of 0.32/2,000 i.e. 0.02% and an ocular comfort rate of 500.00/500 i.e. 100.00%.
The following table presents the obtained results:
Items Results
Irritant ocular 0.00%
. . Mechanical ocular 0.00%
. Functional signs
Physico-chemical ocular 0.00%
.______________________ Palpebral 0.00%
. . Bulbar conjunctival redness No occurrence
Physical signs
________________________ Comeal cells loss No occurrence
: BAiT.
!
Initial Time TO: 7.58 seconds Initial
Time TI0 mm: 6.65 seconds Non
clinically significant modiFication
. Maximal conjunctival index 0.00%
Coloriinetry
Maximal corneal index 0.32%
Contact lenses deposit index 0%
Ocular irritation rate 0.02%
Ocular comfort rate 100.00%
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09 May 2008 34 out of42
The analysis ofthe impact the investigational product has on the ocular structures
allows determining the following characteristics:
Investigational product kinetics Very low contact

Remanence on tear film Unknown
Corneal epithelium -- Practical!v nil toxicity
Bulbar conjunctiva Non toxic
Conjunctival epithelium Non toxic
Lid margin Non toxic
Contact lenses compatibility Very good
Functional tolerance Very good
Investigational product chronic use No foreseeable risk
The ocular functional and physical signs analysis allows considering that the
investigational product shows a practically nil ocular irritant potential, which is very good
for this type of product.
The palpebral functional and physical signs analysis allows to consider that the
investigational product shows a practically nil palpebral irritant potential, which is very
good for this type of product.
XV.2.Investigational product comparison.
The following table shows the different appearance frequencies of ocular irritation
Functional signs for FACE CLEANSERS compared to the one of the investigational
product.
FREQUENCIES OF OCULAR IRRITATION

FUNCTIONAL SIGNS FOR FACE CLEANSERS
Investigational
Minimal Average Maximal
product
frequency frequency frequency
frequency
0.00% 1.28% 16.55% 0.00%
The investigational product presented a very good functional tolerance compared to

other products oF the same kind.

09 May 2008 35 out of42
XV.3. Cutaneous acceptability of the investigational product.
The following table presents the new signs which appeared during the study
Number of %of Freq. Average Grade Grade Grade Grade Grade

occurrences subjects % intensity 1 2 3 4 duration
Cutaneous
2 4.0 0.18 2.00 0 2 0 0 1.4
stinging
Tugging
2 4.0 0.29 1.00 2 0 0 0
eel ing
Erythema 1 2.0 1.00 1 0 0 0
Dryness 3 6.0 1.00 3 0 0 0

I
Desquarnation I 2.0 1.00 1 0 0 0
.______
The following table presents the subject who showed functional irritation signs:
Cutaneous stinging
No CODE ITvpe I Nature Grade I Number
48BIAcEI si M 2 I
Key s: sensitive skin
M : combination skin
The following table presents the subject who showed physical irritation signs:
Ervthema Desquamation*
No Code Type N attire -
(Grade) (Grade)
S GADIS C I I
Key n: non sensitive skin

G: oily skin
: sign already preseni in the beginning olthe study in 1 subject ‘dio felt an irritation
physical sign
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09 May 2008 36 out of42
The following table presents ihe evolution of the signs observed at the beginning of the
study.
Percentages of occurrences
Number of
Increased Decreased Unchanged
occurrences
Discomfort feeling 3 0.0 100.0 0.0
Tugging feeling 10 30.0 70.0 0.0
Erytherna 29 3.4 34.5 62.1
Dryness 8 0.0 62.5 37.5
Roughness 3 0.0 66.7 33.3
Desquarnation 6 0.0 66.7 33.3
Comments
I) Safety
No significant clinical manifestation of intolerance or allergy induced any premature

withdrawal from the study.
(a) Functional signs
The functional signs of irritation corn bine the following signs: cutaneous stinging,
pruritus and burning feeling with an intensity and/or duration meaning an irritation.
The investigational product induced the appearance of an irritation functional sign,

cutaneous stinging, of slight intensity, equivalent duration to I hour (irregular during the
day or not well defined), occurring in only I subject (n48). i.e. 2.0% of the panel, with an
appearance frequency of 0.04%.
‘b Physical signs
The investigational product induced (lie appearance of an irritation physical sign,

erythema, of very slight intensity, occurring in only 1 subject (n°8), i.e. 2.0% of the
panel.
‘c,) Cominenis
The frequency of irritation functional signs is of 0.04%, which is totally acceptable for
this kind of product in this type of subject presenting a combination and sensitive skin.
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09 May 2008 37 out of42
Only I subject i.e. 2.0% of the panel presented an irritation physical sign, which is
totally acceptable for this kind of product, in this type of subject presenting a non
sensitive and oily skin.
(‘ci) Conch, clan
Considering these observations, the investigational product presents a good safety of

use and a very siight cutaneous irritant potential when applied on the face and the
neck in the conditions of this study.
2) Comfort
(a,) Functional signs
New signs
The investigational product induced the appearance of discorn fort functional signs:
• Cutaneous stinging, of slight intensity. short duration (inferior to 10 minutes),
occurring in only I subject(nc44). i.e. 2.0 % of the panel, with an appearance
frequency of 0.15%,
• Tugging feeling, of very slight intensity, occurring in 2 subjects (n°l4 and 24), i.e.
4.0% of the panel. with an appearance frequency of 0.29%.
Evolution of the pre-existing signs

100.0% of the discoin fort feeling present in the beginning of the study decreased during
the observation period.
70.0% of the tugging feeling present in the beginning of the study decreased during the
observation period.
The tugging feeling felt in the beginning of the study by subjects n°4, 8 and IS worsened
during the observation period: from very slight to slight intensity for 2 subjects and
from very slight to moderate intensity for I subject.
(b,) Physical signs
New siens
The investigational product induced the appearance of physical signs expressmg a
modification of the cutaneous state:
• Dryness, of very slight intensity, occurring in 3 subjects in total (n°22, 34 and
43), i.e. 6.0% of the panel,
• Desquam ation, of’ very slight intensity, occurring in only I subject (n°47), i.e.
2.0% olthe panel.
Evolution of the ore-existing signs

96.6% of the erytheina occurrences present in the beginning of the study decreased or
remained unchanged during the observation period.
The erythem a present in the beginning of the study in the subject n°44 worsened during
the observation period: from slight to moderate intensity.
(c? Co,;,mc,us
The frequency of the discom fort functional signs is about 0.4%, which is acceptable for
this kind of product, in this type of subjects with sensitive and combination skin.
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09 May 2008 38 out of42
8.0% of the subjects presented physical signs expressing a modification of the cutaneous
state, which is acceptable for this kind of product, in this type or subjects presenting a
combination, non sensitive skin for I subject and sensitive skin for 3 subjects.
(11) Conclusion
Consequently, the investigational product is considered as comfortable xhen applied

onthe face and the neck in the conditions of this study.
XV.4. Cosmetic acceptability of the investigational product.
The following table presents the percentages of satisfaction (answers ith ‘agree or
‘slightly agree’) and the percentages of dissatisfaction (answers ith ‘slightly disagree
and ‘disagree) obtained for each item.
These results also expressed in number of subjects are calculated in the 50 subjects who
took part in the whole study.
PERCENTAGE OF PERCENTAGE OF
QUESTIONS SATISFACTION DISSATISFACTION STATISTICS
(Number ofsubjects) (Number of subiects)
SENSORY FEATURES
The color of the product is pleasant 94% (47) 6%(3) P3.71E-u S
The texture of the product is P=2.3IEI2 S
96% (48) 4%(2)
pleasant
lie aspect oftir product is R”3.71E-uS
94%(47) 6%(3)
pleasant
lie scent of ite product is pleasant 6SVo(34) 32’/o(16) P0.015 S
APPLICATION
lie product is sy to apply 94% (47) ff/o(3) P=3.7IE-” S
Tie application is
lW’/ (50) (P/o(0) P1.78E-’s S
hornageneois’uni fonri
ACCEFrABI LaY
lie product is comfortable (48)
ckP/0 4%(2) [‘=2.3 I E-’2 S
lie product is suitable fir nr 88¼ (44) l2% (6) l’=3.24E-B S
lie product is suitable fa- ny skin lI.I6ED6S
84%(42) le/0(8)
type
lie product foans well 86¼ (43) 14% (7) P=2. I OE-c7S
lie product is easilyrinsed ofi’ %%(47) 6%(3) I’=3.71E-11S
APPRECIATION
GIdxtIly, tlx product is pleasant 9Y/o(46) g)/(4) P=4.46E-’o S
Key: S = Significant dilTcrence
The investigational product obtains very good percentages of satisfaction ranging between
68% and 100%.
The almost all items obtain percentages superior to 80%.
92% of the subjects agree or slightly agree on the fact that globally, the investigational
product is pleasant.
4717-43-OD I Rapp TO! ±Acc cosm vI

09 May 2008 39 out of42
/f
74% of the subjects would like to continue using the investigational product and 58%
would purchase it.
The statistical analysis reveals a significant difference between percentages of

satisfaction and percentages of dissatisfaction for all proposed items.
4717-43-ODI Rapp ml -1-Ace cosm vi

09 May 2008 40 out of 42
XVI. CONCLUSION.
In the conditions of the study, the investigational product

MENTHA PIPERITA (PEPPERMINT) LEAF WATER 50% Cleansing Gel LOT Ll7492694 DU
10/12/2007:
Presents a very good ocular corn fort, a very good ocular safety
and a very good global ocular tolerance in subjects presenting
sensitive eyes, non-sensitive eyes and contact lenses wearers,
Presents a very good palpebral tolerance.
Presents a very good compatibility with the contact lenses.
Presents a good cutaneous tolerance, on the face and the neck, in

subjects presenting a corn bination to oily skin among which 44% of
them with a sensitive skin.
Obtains a very good appraisal of its cosm etic acceptability.
XVII. SIGNATURES.
The study described in this report was carried out according to the protocol, to
PERITESCO SOP and to lCl-I Topic E6 <(Note for guidance on Good Clinical Practice
CPMP/ lCl-l/ 135/ 95 .
I assume the responsibility of the data validity.
‘t/u/ 3
dr. M. PERICOI date
Ophthalmologist
Main investigator
PERIT CO
12.05.2008
Dr. S. LAQUIEZE
date
Dermatologist
Co-invest i gato”
PERITESCO
Dr.M. RAFAA
Dermatologist
Co-investigator
PER ITESCO
471 7-43-nD I Itq’p Tol —Ace cosm vi
09 May 2008 41 out oI’42
4-FRONT
‘WREsEARcH
SvyreporIdaIe: 17-MAR.2008
INTE}JALREFERENCE EW_R_5iDCLLND53O12.aDc
NvsrioAr:Ns:AsoRAroay SIIJOYNLM5ER 49DRM.PAT-Ca22
STUOYNUMBER 0T026341
STUDY REPORT
SINGLE PATCH TEST
InvestigationalProductNumber MENTHA PIPERITA (PEPPERMINT) LEAF

WATER 50% Cleansing Gel
Type of investigational product
Batch Number: Lot nt17492694 du

1 0/1 2/2007
Document status Final
Standard protocol FN p cm flit NP Ffl1 nrrpntvprcinn
Study population: F-thysueds allskintypes.betn 18 and 7Oyears sage
First Subject,firstvisit 04-FEB-2008
last SubjectIast visit: 1 1-FEB-2008
Study Sponsor
Study Monitor Toxicologist
12-14 meDesnouettes
Investigating laboratory 7501 SPans
ir 33(0)153684657
i[Ill 33 (0)15365.79.05
Investigating laboratory site Desnouettes
Investigator — DrDrouault
Dermatologist
ir 33(0)1.53.65.79.02
P1 of 23
Sludyreporwa?e:1 7-MAR-2008
INTERMAL REFERENCE Rappon MENTHA PIPERITA (PEPPERMrNTI LEAF WATER 50% CIoan.rna Gel
INVESTIGATING lABORATORY STUDY NUMEER 49-DRM-PAT-08-O8

STUDYNUMBER DT026341
STUDY SYNOPSIS
Investigational
product identification MENTHA PIPERITA (PEPPERMINT) LEAF WATER 50% Cleansing
Gel
Lotnt17492694 du1011212007
Investigating Laboratory Study 49-DR M -PAT-0 8-08

number
Study number D TO 2 6 3 4 1
From 04-FE8-2005 toll -FEB-2008
Study period
To confirm on humans the skin compatibility of cosmetic products to volunteer
Objective subjects, under exaggerated conditions of exposure
52 subjects enrolled
Number of Subjects 52 subjects analyzed
DO: Patch application ofthe product

Methodology 02: Patch removal(48h afterapplication)
Readingand scoring (30 to 60 minutes afterpatch removal)
D3: Readingand scoring (24 (+1-3) bourn after patch removal)
D4: Readingandscoring(48 (+1-4) hours afterpatch removal)
Scores calculation and interpretation of the results
EN_P_STD_CLUNP 5001, current version.

Standard protocol No modification to standard protocol referenced EN_P_STD_CLuNP_500 in.
Modification to study protocol current version was observed
Investigating Dermatologist Dr Yorik Drouault
Safety results READING SCORES

A I
TIMES 0 I 2 3 4 5 6
02 38 12 2 0 0 0 0 011
03 31 18 3 0 0 0 0 0.46
D4 46 6 0 0 0 0 0 0.12
GIl. 0.295
Conclusion In the conditions of the study and aftera single 46h-app!icaton underexaggerated
conditions, the skin compatibility of investigationalproduci
MENTHA PIPERITA (PEPPERMINT) LEAF WATER 50% Cleansing Gel
Lot n’L17492694 du 1011212007 (product applied 10 % diluted in distilled
waterunder ocdusive patch) can be considered as good.
4-FRONT
RESEARCH
2 of23
Study reporldale: 1 7.MAR-2008
lN14°Lara Rapport MENTHA PIPERITA (PEPPERMINT) LEAF WATER 50% Cleansing Gel
49-DRM-PAT-OB-OB
SUui’NUMBER DT026341
INVESTIGATING DERMATOLOGIST STATEMENT
This study was conducted in conformity with the General Standard Operating Procedures (SOPs) of the
Investigating laboratory. the current version of Standard Protocol (4) and in the spirit of the general
principles of the Good Clinical Practices published by l.CH. Topic E6 (ICH Harmonized tripartite Guideline
for Good Clinical Practices having reached Step 5of the ICH Prucess at the ICH Steering Coninittee meeting
on I May 1996)0).
I cbiaEThths ‘n [is aijrt dte ptIsldloi& &iir yD th4’ ai-gift

atnead1ThfiJ ia.sjd dnyoAndteas
lhsrqxit iswiue, in eihtdteg tsJ piräpi cffreGnJOric RatispiJi b,’l.C.H.

E3(2).
Dr Yorik Drouault:
Date: 25 Mar 2Q8 Sig nature:
4-FRONT
RESEARCH 3 o123
RuppD
Studyreporldale:17-MAR-2006
MENTHA P]PERJTA (PEPPERMINT) AF WATER 5D CIeansLn; Gel
I
I Ir*sucaGLaacMmysnmruvHs 49-DRM-PAT-DB-OB
DT026341
STWI’NUMBER
QUALITY ASSURANCE STATEMENT
Audits peffonned are described below:
Typeof audit Date of audit Date of reportto the Investigator
Not applicable (report to general

Processus: study management 31 /JAN/2007
manager)
Typeof audit Date of audit Date of reportto the Investigator

Report(vs.rawdata) 2 1/MARJ200B
manager)
Not applicable (reportto general
Infonned consent 21/MARI2008
manager)
TrialMaster Ale 21 /MAR/200s
manager)
Audits were performed in compliance with the general procedures of Quality Assurance department and in
the spirit of “Good Practices” and of the general pñnciples of the Good Clinical Practices published by I.C.R
Topic E6 and E3(1 ;2)
Each step of the study was controlled by project team accordingto internal procedures.
This report constitutes a true and faithful record of the original raw data of the investigating laboratory,
generated during the perfonnance of the study.
Date: 2. La’2
Name,qualifications C. TOMKIEWICZ
QA Manager
- --‘ 4-FRONT
RESEARCH 4of23
Studyreporldale. 1 7-MAR.2008
INTERNAL REFERENCE Rapport MENTHA PIPERITA (PEPPERMINt LEAF WATER 50% Cleanhino Gel
IIWESTIGATING lABORATORY SIUDY NUMBER 49-DRM-PAT-O8-08
SIUDYNUMBER DTD26341
D4 (Reading)
- This readingtook place 48 (+/-4) hours after patch removal.
- The investigating dermatologist questioned the subjects about any changes in their health and on
any medication taken since their last visit.
- The investigating dermatologist carefully examined the test areas and graded the reactions using
the same specific gradingscale.
6.6. Clinical study: Evaluation ofthe skin compatibility
6.6.1. Grading
Patched sites were graded as follows:
• Theflrst gradingwes made at 30 to 60 minutes after removalof the patches,
• Othergradings were rmde 24 (4/- 3), and4s (+/- 4) hours after removalof the patches,
• Additionalsessions occurred for6 subjects.
• All adverse reactions were graded until resolution.
As an accurate description of the test sites is a crucial point, each test site was observed and palpated to
assess infiltration.
Grading was performed using a day-light illuminator (D 65 North daylight or equivalent) and according to
the following steps (11; 12; 13; 14):
1.Evaluation of erythema and evaluation of the presence of palpable elevated lesions
2. Description of the chosen grade
3. Description of other aspects concerning the test site
The possible cutaneous reactions were evaluated for investigational product M ENTHA
PIPERITA (PEPPERM INT) LEAF WATER 50% Cleansing Gel Lot n°L17492694 du 101121 2007,
for each subject, accordingto the following numerical scale:
No reaction 0
Mild erythema or barely visible or spotty or moderate with not well defined edges 1
Moderate erythema, with well defined edges 2
Severe erythema or spreading beyond lest site 3
Cedema or papules with or without erythema 4
Qedema and vesicles or bullae with or without erythema 5
Caustic reaction (ulceration) 6
No doubtful reaction was observed.
4-FRONT
‘rnEsEARcH 18of23

Amended Safety Assessment of Mentha Piperita (Peppermint) - Derived Ingredients As Used in Cosmetics

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Amended Safety Assessment of

Mentha Piperita (Peppermint)-derived Ingredients as Used in

Status: Re-review for Panel Review

© Cosmetic Ingredient Review

To: CIR Expert Panel Members and Liaisons

Public Comment CIR Expert Panel Re-Review Rpt Status

Are new data cause to reopen? 4 ingredients in original

IDA Notice IDA

Draft FAR DRAFT FINAL

Table Different Conclusion

Final Amended Issue

CIR History of:

Mentha Piperita-derived Ingredients

Re-review document, Teams/Panel: April 10-11, 2017

Other Relevant In Vivo-Animal

[Mentha Piperita-derived Ingredients (5/16/2016; 2/5/2017]

FDA databases – http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm (CFR); then,

Botanical Websites, if applicable

Fragrance Websites, if applicable

RIFM (the Research Institute for Fragrance Materials) should be contacted

Day 2 of the June 3-4, 1996 CIR Expert Panel Meeting

(1) Concentration of use

Day 2 of the December 16-17, 1996 CIR Expert Panel Meeting

Peppermint (Mentha piperita) Oil, Peppermint (Mentha piperita) Extract,

(1) Concentration of use

Peppermint (Mentha Piperita) Oil

(1) Concentration of use

Dr. Bronaugh said that 2 mg is approximately 2 l, which is a small amount.

Day 2 of the September 22-23, 1997 CIR Expert Panel Meeting

Peppermint (Mentha Piperita) Oil,

Day 2 of the March 19-20, 1998 CIR Expert Panel Meeting

Peppermint (Mentha Piperita) Oil,

Day 2 of the September 10-11, 1998 CIR Expert Panel Meeting

Peppermint (Mentha Piperita) Oil,