Safety Assessment of Dioscorea Villosa (Wild Yam) Root Extract

as Used in Cosmetics

Status: Re-Review for Panel Consideration

Release Date: February 10, 2023
Panel Meeting Date: March 6-7, 2023

The Expert Panel for Cosmetic Ingredient Safety members are: Chair, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito,
M.D.; David E. Cohen, M.D.; Curtis D. Klaassen, Ph.D.; Allan E. Rettie, Ph.D.; David Ross, Ph.D.; Thomas J. Slaga, Ph.D.;
Paul W. Snyder, D.V.M., Ph.D.; and Susan C. Tilton, Ph.D. The Cosmetic Ingredient Review (CIR) Executive Director is Bart
Heldreth, Ph.D. This safety assessment was prepared by Preethi Raj, Senior Scientific Analyst/Writer, CIR.

© Cosmetic Ingredient Review

1620 L Street, NW, Suite 1200 ♢ Washington, DC 20036-4702 ♢ ph 202.331.0651
cirinfo@cir-safety.org
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Commitment & Credibility since 1976

Memorandum

To: Expert Panel for Cosmetic Ingredient Safety Members and Liaisons
From: Preethi S. Raj, M.Sc., Senior Scientific Writer/Analyst, CIR
Date: February 10, 2023
Subject: Re-Review of the Amended Safety Assessment of Dioscorea Villosa (Wild Yam) Root Extract

The Expert Panel for Cosmetic Ingredient Safety (Panel) published a review of the safety of Dioscorea Villosa (Wild Yam)
Root Extract in 2004, with a conclusion that this ingredient is safe for use in cosmetic products
(originalreport_WildYam_032023). In the Discussion of that report, the Panel further clarified that this conclusion is valid
only for extracts prepared in a manner that produces a similar chemical profile as that described in the safety assessment,
particularly in regard to diosgenin (i.e., an expected upper limit of 3.5%). Additionally, the Panel stated that extracts not
prepared in a manner that produces a similar chemical profile would be considered safe if they have a similar safety test
profile.

It should be noted that in 1999 a final report was issued, but never published, with an insufficient data conclusion.
However, the 1999 report is not included for review because all of the data appear to have been repeated in the 2004 report.

Because it has been 15 years since the final amended report was published, in accordance with Cosmetic Ingredient Review
(CIR) Procedures, the Panel should consider whether the safety assessment of Dioscorea Villosa (Wild Yam) Root Extract
should be re-opened. An extensive search of the world’s literature was performed for studies dated 1999 forward. An
historical overview, comparison of original and new use data, search strategy, and relevant data found are enclosed herein
(newdata_WildYam_032023).

Notable findings include two short-term oral toxicity studies and a 13-wk oral toxicity study in which the NOAEL for both
rat sexes was determined to be the maximum received dose of 5000 mg/kg/d. Additionally, studies demonstrating the
potential cytotoxicity of Dioscorea villosa (wild yam) root extract against breast cancer cell lines, anti-inflammatory
effects, and a clinical study in which no significant side-effects or metabolic/endocrinal changes were seen with the 3-mo,
topical application of wild yam cream in healthy premenopausal women, were found.

Also included for your review is a table of current and historical use data (usetable_WildYam_032023). (As per the Panel’s
request at the December 2022 meeting, an updated use table format has been implemented. The frequency and
concentration of use is presented both cumulatively by likely duration and exposure and individually by product category.)
The reported frequency of use has increased from 1 to 43 uses since the last review; however, the reported concentration of
use has decreased. The maximum reported use concentration of Dioscorea Villosa (Wild Yam) Root Extract in 1999 was
15% (0.5% maximum solids from wild yam) in moisturizing formulations; in 2022, this ingredient is reported to be used at
0.3% in non-spray moisturizing products.

If upon review of the new studies and updated use data the Panel determines that a re-review is warranted, a Draft
Amended Report will be presented at an upcoming meeting.

__________________________________________________________________________________________
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(Main) 202-331-0651
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Re-Review - Dioscorea Villosa (Wild Yam) Root Extract - History and New Data
(Preethi Raj – March 2023 meeting)

Ingredients (1) Citation Conclusion Use - New Data Results Use - Existing Data Results Notes
Dioscorea Villosa (Wild 1999: FR, not published Insufficient data frequency of use (2022) 43 frequency of use (1998) 1 frequency of use increased, but concentration of
Yam Root Extract conc of use (2022) 0.3% conc of use (1999) 0.00001 – 15% use decreased (was reported at up to 15% in
IJT 23(S2): 49-54, 2004 safe as used moisturizing creams, lotions, powders, and
Changes to Original List (amended sprays in 1999, and at 0.3% in non-spray
None conclusion) moisturizing body products in 2022)

New use categories in 2022: 2 new uses near the

eye, 1 non-coloring hair preparation, and 1
mucous membrane use

NOTABLE NEW DATA

Publication Study Type Results – Brief Overview Different from Existing Data?
Toxicity
Lima CM, et al. Acute toxicity Groups of male and female rats (6/group) received either water (control), or a single no
Bioassay-guided evaluation dose of up to 5 mg/kg dried extract of Dioscorea villosa (wild yam) root extract in
of Dioscorea villosa - an water, via gavage. No animals died during the 14-d observation period, and no changes
acute and subchronic in body weight or internal organ weights was observed. Soft feces was observed in both
toxicity, antinociceptive and experimental and control animals, and was not attributed to the acute exposure.
anti-inflammatory approach.
BMC Complement Altern
Med. 2013 Jul 28;13:195.
Wojcikowski K, et al. Short-term toxicity, Groups of male Sprague-Dawley rats (n=4) were fed normal rat chow (controls) or No short-term oral toxicity in original report
Dioscorea villosa (wild yam) oral chow combined with 0.72% dried ethanolic Dioscorea villosa (wild yam) root extract
induces chronic kidney injury for 7, 14, or 28 d, and specifically observed for effects on the kidney and liver. No
via pro-fibrotic pathways. acute renal or hepatoxicity was observed. An increase in kidney fibrosis and
Food Chem Toxicol. 2008 inflammation in the livers of rats consuming the extract for 28 d was observed.
Sep;46(9):3122-31.
Lima CM, et al. Short-term toxicity, Groups of male and female rats (10/group) received either water (control) or 1000 No subchronic oral toxicity in original report
Bioassay-guided evaluation oral g/kg/d dried Dioscorea villosa (wild yam) root extract, in water, via gavage, for 30 d.
of Dioscorea villosa - an Both experimental males and females exhibited weight gain at rates significantly higher
acute and subchronic than control animals (p < 0.0001); this effect was attributed to the possible effect of the
toxicity, antinociceptive and extract as a precursor of progesterone and corticoids, which can cause water retention.
anti-inflammatory approach. The extract was not considered toxic under the conditions of this study.
BMC Complement Altern
Med. 2013 Jul 28;13:195.
Cha SB, et al. A 13-week Subchronic toxicity, Rats were administered 0, 800, 2000, or 5000 mg/kg/d of an aqueous Dioscorea villosa No subchronic oral toxicity in original report
subchronic toxicity study of a oral (wild yam) root extract, via gavage, for 13 wk. At dose levels ≥ 2000 mg/kg/d, an
Dioscorea Rhizome water increased incidence of zona glomerulosa hypertrophy and hyperplasia in the adrenal
extract in rats. Regul Toxicol gland was observed in both sexes. No treatment-related adverse effects on clinical
Pharmacol. 2021 signs, body weight, food and water consumption, ophthalmic examination, urinalysis,
Mar;120:104844. hematology, or organ weights were observed at any dose. The NOAEL for both sexes
was determined to be 5000 mg/kg/d.

1
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NOTABLE NEW DATA

Publication Study Type Results – Brief Overview Different from Existing Data?
Anti-carcinogenicity
Mazzio E, et al. Effects of Anti-carcinogenicity The cytotoxic potential of a crude ethanolic Dioscorea villosa (wild yam) root extract No data on anti-carcinogenicity in the original
wild yam root (Dioscorea was evaluated in MDA-MB-231 triple-negative breast cancer cell lines at 0, 18.5, 37, report
villosa) extract on the gene 74, 148, 296, or 592 µg/ml when incubated for 24 h. A dose-response relationship was
expression profile of triple- observed; at concentrations > 148 µg/ml there was near complete cell death.
negative breast cancer cells.
Cancer Genomics
Proteomics. 2021 Nov-
Dec;18(6):735-755.
Aumsuwan P, et al. Anti-carcinogenicity Two breast cancer cell lines, MCF-7 (estrogen receptor positive) and MDA-MB-231 No data on anti-carcinogenicity in the original
Evaluation of wild yam (estrogen receptor negative) were treated with a methanolic extract of Dioscorea villosa report
(Dioscorea villosa) root (wild yam) root powder (0-50 µg/ml) for 72 h. Treatment with the extract reduced cell
extract as a potential viability in both cell lines and altered mRNA and DNA methylation patterns, having an
epigenetic agent in breast epigenetic effect on promoter regions and expression of the GATA3 gene (a potential
cancer cells. In Vitro Cell breast cancer biomarker).
Dev Biol Anim. 2015
Jan;51(1):59-71.
Anti-inflammatory
Lima CM, et al. Anti-inflammatory Mice received a 500 µg/cavity injection of carrageenan in the peritoneal cavity, 1 h after No anti-inflammatory data in original report
Bioassay-guided evaluation effects administration of 100, 200, or 400 mg/kg dried Dioscorea villosa (wild yam) root
of Dioscorea villosa - an extract, in 0.9% saline with two drops of Tween 80, or dexamethasone (positive
acute and subchronic controls). After injection with phosphate buffered saline, fluid was collected
toxicity, antinociceptive and immediately and leukocyte migration was measured. Significant inhibition of
anti-inflammatory approach. carrageenan-induced leukocyte migration to the peritoneal cavity 4 h after exposure was
BMC Complement Altern observed in all dose groups (40.41, 32.96, and 31.66%, respectively).
Med. 2013 Jul 28;13:195.
Clinical Studies
Komesaroff PA, et al. Hormonal effects A double-blind, placebo-controlled, cross-over study was conducted to examine the No clinical data in original report
Effects of wild yam extract effects of a applying a topical wild yam cream and a placebo in 23 healthy menopausal
on menopausal symptoms, women. After 3 mo of treatment, no significant side-effects or changes in weight,
lipids and sex hormones in systolic or diastolic blood pressure, total serum cholesterol, triglycerides, HDL, FSH,
healthy menopausal women. glucose, estradiol, or serum and salivary progesterone were observed.
Climacteric. 2001
Jun;4(2):144-50.

2
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Search (from 1999 on)

PubMed
dioscorea villosa wild yam root extract – 164/5
dioscorea villosa root extract steroid- 58/3
dioscorea villosa root extract estrogen – 6/0
dioscorea villosa root extract progesterone – 1/0
(((((((((((((dioscorea villosa extract) OR (dioscorea villosa root extract)) OR (dioscorea villosa rhizome extract)) OR (wild yam extract)) OR (mexican wild yam)) OR
(rheumatism root)) OR (devil's bones)) OR (mexican yam)) OR (atlantic yam)) OR (china root)) OR (colic root extract)) OR (extract of colic root)) OR (extract of discorea
villosa)) OR (yuma) AND (1999:2023[pdat])– 54,670/5
(Aecopuree Purple Yam) OR (AEC Wild Yam Root Extract Powder) – 26/0
((((((((((((((((((((((((((((((((actigen y) OR (actiphyte of yam BG50)) OR (actiphyte of yam GL50)) OR (actiphyte of yam lipo S)) OR (actiphyte of yam PG50)) OR (activated
botanicals estroherb complex)) OR (CO actiphyte of wild yam AL)) OR (CO actiphyte of wild yam GL)) OR (CO actiphyte of wild yam lipo O)) OR (CO actiphyte of wild
yam lipo RS)) OR (CO actiphyte of wild yam lipo sun)) OR (dioscorea villosa (wild yam) root extract ies)) OR (FMLT psoriasolve)) OR (FMLT psoriasolve1)) OR (FMLT
sebocure)) OR (FMLT sebocure1)) OR (herbex wild yam extract)) OR (multiex lipo phytogenix)) OR (multiex phytomax (lipo))) OR (multiex sapomax)) OR (nlt diosphere
2.0)) OR (premier wild yam root 10% extract)) OR (unisteron y-50)) OR (viazest yam OS)) OR (vt-218 extract of wild yam)) OR (wild yam)) OR (wild yam extract HG 595))
OR (wild yam extract HS 3705 G)) OR (wild yam extract huileux)) OR (wild yam extrait huileux)) OR (wild yam HPT titrated)) OR (wild yam HS)) OR (wild yam LS) AND
(1999:2023[pdat]) – 2,530/3
General Web search
dioscorea villosa (wild yam) root extract toxicity- 34,500/2
dermal sensitization dioscorea villosa wild yam root extract – 13,600/0
dermal irritation dioscorea villosa wild yam root extract – 13,200/0
inhalation toxicity dioscorea villosa wild yam root extract – 8,450/0

3
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Table 1. 2022 and historical frequency and concentration of use according to likely duration and exposure and by product category
# of Uses Max Conc of Use (%)
Dioscorea Villosa (Wild Yam) Root Extract
20221 19982 20223 19992
Totals 43 1 0.3 0.00001-15
summarized by likely duration and exposure*
Duration of Use
Leave-On 39 1 0.3 0.00001-15
Rinse-Off 4 NR NR NR
Diluted for (Bath) Use NR NR NR NR
Exposure Type**
Eye Area 2 NR NR NR
Incidental Ingestion NR NR NR NR
Incidental Inhalation-Spray 25 a ; 10 b 1b NR 15; 0.00001 b
Incidental Inhalation-Powder 10 b 1b NR 0.00001 b
Dermal Contact 42 1 0.3 0.00001-15
Deodorant (underarm) NR NR NR NR
Hair - Non-Coloring 1 NR NR NR
Hair-Coloring NR NR NR NR
Nail NR NR NR NR
Mucous Membrane 1 NR NR NR
Baby Products NR NR NR NR
as reported by product category
Eye Makeup Preparations
Eye Lotion 2 NR NR NR
Hair Preparations (non-coloring)
Tonics, Dressings, and Other Hair Grooming Aids 1 NR NR NR
Personal Cleanliness Products
Other Personal Cleanliness Products 1 NR NR NR
Skin Care Preparations
Cleansing 2 NR NR NR
Face and Neck (exc shave) 6 NR NR NR
Body and Hand (exc shave) 4 1 NR 0.00001 (0.000002%
maximum solids from wild yam)
Moisturizing 23 NR 0.3 (not spray) 15 (0.5% maximum solids from
wild yam)
Night 1 NR NR NR
Paste Masks (mud packs) 1 NR NR NR
Other Skin Care Preparations 2 NR NR NR

NR – not reported
*likely duration and exposure is derived based on product category (see Use Categorization https://www.cir-safety.org/cir-findings)
**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.
b
Not specified whether a spray or a powder, but it is possible the use can be as a spray or a powder, therefore the information is captured in both categories

REFERENCES

1. U.S. Food and Drug Administration Center for Food Safety & Applied Nutrition (CFSAN). 2022. Voluntary Cosmetic Registration
Program - Frequency of Use of Cosmetic Ingredients (VCRP). (Obtained under the Freedom of Information Act from CFSAN;
requested as "Frequency of Use Data" January 4, 2022; received January 11, 2022.)

2. Final report of the amended safety assessment of Dioscorea Villosa (Wild Yam) root extract. Int J Toxicol. 2004;23 Suppl 2:49-54.

3. Personal Care Products Council. 2022. Concentration of Use by FDA Product Category: Dioscorea Villosa (Wild Yam) Root Extract.
(Unpublished data submitted by the Personal Care Products Council on October 31, 2022.)
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Final Report of the Amended Safety Assessment

of Dioscorea Villosa (Wild Yam) Root Extract1

tion method, but not using a preincubation method. Although the

Dioscorea Villosa (Wild Yam) Root Extract is an extract of the concentration at which the actual plant extract is used in cosmetic
rhizomes of the wild yam, D. villosa. A manufacturing process was products is low, one of the primary safety concerns with this plant
described in which cut up and ground rhizomes are combined with extract is the possible metabolic/endocrine activity, e.g., estrogen-
an eluant (e.g., oleyl alcohol), the plant material precipitated with like or progesterone-like activity as a result of the presence of small
addition of a miscible solvent, washed, and redissolved in the orig- amounts of plant phytosterols such as diosgenin. Extracts prepared
inal eluant. The extract contains glycoside and steroidal saponins as described in this safety assessment, with an upper limit of 3.5%
(≤0.4%), diosgenin (≤3.5%), alkaloids, tannins, phytosterols, and diosgenin, did not have any estrogenic activity, demonstrating that
starch. Levels of heavy metals, 1,4-dioxane, chloroform, methy- it is possible to produce material that does not present this specific
lene chloride, trichloroethylene, and benzene are reported to be safety concern. Although extracts from pesticide-free plants were
below limits of detection. Although only one use was reported to not considered genotoxic and it was the view of the Cosmetic In-
the U.S. Food and Drug Administration (in a body and hand prepa- gredient Review (CIR) Expert Panel that there do not appear to
ration), industry reported uses in body and hand creams, lotions, be any components that could be carcinogenic, pesticide residues
powders, and sprays at a concentration of 0.00001% (equivalent could raise this issue. It was urged that manufacturers limit pes-
to 0.000002% plant solids), and in moisturizing creams, lotions, ticide residues to the limit previously used for lanolin of not more
powders, and sprays at concentrations up to 15% (equivalent to than 40 ppm (with not more than 10 ppm for any one residue).
0.5% plant solids). Preparations from D. villosa are used in herbal Based on these data, it was concluded that Dioscorea Villosa (Wild
medicine for treatment of a variety of ailments and by the pharma- Yam) Root Extract is safe as used in cosmetic formulations. This
ceutical industry in the preparation of steroids. Using Dioscorea conclusion regarding safety, however, is valid only for extracts pre-
Villosa (Wild Yam) Root Extract prepared via a specified process, pared in a manner that produces a similar chemical profile as that
it is possible to produce a stable extract with a narrow range of described in this report, particularly as regards diosgenin. Extracts
diosgenin content. The extract produced using this methodology not prepared in a manner that produces a similar chemical profile
was tested in acute and short-term toxicity tests, dermal irritation would be considered safe if they have a similar safety test profile.
tests, a sensitization test, an ocular irritation test, a rat uterotropic
assay, and genotoxicity tests. An acute oral toxicity test produced
hypoactivity, piloerection, and dyspnea and a death in 1 of 10 rats
at 2 g/kg using the specified extract, but no toxicity in rats given INTRODUCTION
0.5 g/kg. A dermal toxicity test using the specified extract demon- Dioscorea Villosa (Wild Yam) Root Extract is an extract of the
strated no acute toxicity in rats. Both a 7-day local tolerance test
and a 28-day dermal toxicity test in rats produced no significant
rhizomes of the wild yam, Dioscorea villosa (Pepe, Wenninger,
adverse effects at the maximum tested concentration of 10%. A sin- and McEwen 2002). The safety of this ingredient was initially
gle application of undiluted extract to the intact and abraded skin reviewed by the Cosmetic Ingredient Review (CIR) Expert Panel
of rabbits produced sufficient irritation for the test material to be with the conclusion that the available data were not sufficient
rated “irritant,” but a 10% dilution was not irritating. Undiluted to support the safety of this ingredient in cosmetic products
extract was only mildly irritating to the conjuctiva of the rabbit
eye; irritation in the iris and cornea was mild and transient. Undi-
(CIR 1999), but additional data were provided by one supplier,
luted extract was not irritating during the induction phase of a including safety test data on a well-characterized product. On
guinea pig sensitization study, nor did challenge with a 25% dilu- the basis of these new data, the CIR Expert Panel has reached an
tion elicit any sensitization. The specified extract at concentrations amended conclusion regarding the safety of Dioscorea Villosa
up to 500 mg/kg/day did not have any estrogenic activity in the ju- (Wild Yam) Root Extract in cosmetic products.
venile rat uterotrophic assay. Genotoxicity assays in bacterial and
mammalian systems were negative, except that Ames test strain
TA 1537 was positive at one dose level using the plate incorpora- CHEMISTRY
Definition
As described by the Cosmetic, Toiletry, and Fragrance Asso-
Received 12 February 2004; accepted 4 June 2004.
1 Reviewed by the Cosmetic Ingredient Review Expert Panel. This report was
ciation (CTFA) and listed in the International Cosmetic Ingre-
prepared by Eric Hooker, Scientific Analyst and Writer. Address correspondence dient Dictionary and Handbook, Dioscorea Villosa (Wild Yam)
to Eric Hooker, 1101 17th Street, NW, Suite 310, Washington, DC 20036, USA. Root Extract (CAS no. 90147-49-2) is an extract of the rhizomes
E-mail: info@cir-safety.org of the wild yam, D. villosa (CTFA 1999a; Pepe, Wenninger, and

International Journal of Toxicology, 23(Suppl. 2):49–54, 2004

Copyright c Cosmetic Ingredient Review
ISSN: 1091-5818 print / 1092-874X online
DOI: 10.1080/10915810490499055 49
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50 COSMETIC INGREDIENT REVIEW

McEwen 2002). Dioscorea Villosa (Wild Yam) Root Extract TABLE 1

is also known as Colic Root Extract; Extract of Colic Root; Eluants and miscible solvents used in preparing Dioscorea
Dioscorea Villosa Extract; Extract of Dioscorea Villosa; Wild Villosa (Wild Yam) Root Extract (Active Organics 2000a)
Yam Extract; and Extract of Wild Yam (Pepe, Wenninger, and
McEwen 2002). D. villosa is also known as wild yam (Polunin Eluant Miscible solvent
and Robbins 1992), Mexican wild yam (Ritchason 1995; Ody Oleyl alcohol Propylene glycol (± water)
1993), colic root, rheumatism root (Ritchason 1995; Polunin and Isocetyl alcohol Butylene glycol (± water)
Robbins 1992), and devil’s bones (Ritchason 1995). Other com- Isostearyl alcohol Glycerin (± water)
mon names include Mexican yam, Atlantic yam, China root, and Ethanol Water
yuma (CTFA 1999a). Hexyldecanol Safflower oil

Physical and Chemical Properties 45◦ C (Active Organics 2000d, 2000e). Stability of the ingredient
Only limited data are available describing the properties of in oleyl alcohol was demonstrated by a comparison of a lot
this ingredient. According to CTFA (1999a) Dioscorea Villosa prepared in 1998 (stored at room temperature) and reanalyzed
(Wild Yam) Root Extract has a pH of 4.0 to 6.8, refractive index in 2000; showing close agreement in distribution of peaks, with
of 1.362 to 1.47 (25◦ C), and specific gravity of 0.90 to 1.06 many of the differences related to the oleyl alcohol peaks (Active
(25◦ C). Organics 2000e).

Manufacture and Production

Composition
Dioscorea Villosa (Wild Yam) Root Extract is prepared by
Wild yam (D. villosa) contains glycoside saponins (Mowrey
grounding and cutting the dried rhizomes/root and extracting
1986), steroidal saponins, diosgenin, alkaloids, tannins, phyto-
this material with water/alcohol (denatured) (CTFA 1999a). The
sterols, and starch (Ody 1993).
plant material is further extracted by maceration or percolation
At a concentration of 1% to 2% plant material, Dioscorea
with solvents, and the maceration process generally lasts 3 or
Villosa (Wild Yam) Root Extract contained 0.4% steroidal sapo-
more days. The solvents and extractibles are filtered. The water
nins (CTFA 1999a). The concentration of other components of
and alcohol can be removed by distillation and the remaining
raw material in Dioscorea Villosa (Wild Yam) Root Extract as
material is diluted to strength with the solvent of choice (usually
sold to the trade is 97% to 99.5% solvents. The other com-
propylene glycol, but butylene glycol, glycerin, water, vegetable
ponents included the solvents water:alcohol, propylene glycol,
oil, or alcohol can be used).
propylene glycol:water, butylene glycol, butylene glycol:water,
Active Organics (2000a) provided additional detail to this
glycerin, glycerin:water, safflower oil, and vegetable oil and 1%
general process. Rhizomes grown pesticide-free are ground and
of the preservatives phenonip or phenoxyethanol. Other contam-
combined 1:1 (w/w) with a specified eluant. The phytochemical
inants are not known, but the following are below the limit of
constituents in the eluant are precipitated by adding a misci-
detection: 1,4-dioxane (<50 ppm), benzene (<50 ppm), chloro-
ble solvent in which the phytochemicals are not soluble. The
form (<25 ppm), methylene chloride (<50 ppm), trichloroethy-
precipitate is washed with water and redissolved in the speci-
lene (<50 ppm), heavy metals, i.e., lead (<20 ppm), arsenic
fied eluant. Assays are conducted for particular phytochemical
(<3 ppm), and iron (<100 ppm).
constituents (e.g., diosgenin), then diluted to the desired concen-
tration with the specified eluant. The maximum concentration of
diosgenin is stated to be 3.5% (CTFA 2000). Measured values Ultraviolet Absorption
of diosgenin were 3.1% with hexyldecanol as the eluant (Ac- Dioscorea Villosa (Wild Yam) Root Extract was stated to
tive Organics 2000b) and 2.7% with oleyl alcohol as the eluant have very low absorption at short wavelengths (CTFA 1999a).
(Active Organics 2000c). Preservatives may be added. Actual absorption between 200 and 700 nm was determined us-
Table 1 lists the eluants and miscible solvents which may be ing a double beam spectrophotometer (Centre Internationale de
used in the above procedure. Toxicologie [CIT] 2000a); λmax was 232 nm (in the UVC region)
and the absorbance (λmax ) was 0.41 AU for a 0.106 g/L solu-
Analytical Methods tion. The peak trailed up to and past 300 nm, but no significant
This ingredient may be characterized by high-performance absorption occurred above 250 nm.
liquid chromatography (HPLC) or gas chromatography (GC)
(Active Organics 2000d, 2000e). Data using these techniques USE
demonstrate that most of the peaks detected relate to the eluant
(hexyldecanol and oleyl alcohol were used), that plant material Cosmetic
can be determined from overlays of the eluant alone and the Dioscorea Villosa (Wild Yam) Root Extract is reported to
extract, and that the plant materials do not degrade with time at function as skin-conditioning agent; other uses are “trade secret”
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DIOSCOREA VILLOSA (WILD YAM) 51

in cosmetic formulations (CTFA 1999a). The product formula- were evaluated at days 1, 7, and 14. Animals were subjected
tion data submitted to the Food and Drug Administration (FDA) to necropsy on day 15; macroscopic examination of internal or-
in 1998 reported that Dioscorea Villosa (Wild Yam) Root Ex- gans (stomach, interstines, heart, kidneys, liver, lungs, pancreas,
tract was used in one cosmetic formulation, a body and hand spleen) was performed.
preparation (FDA 1998). Hypoactivity, piloerection, and dyspnea were observed in all
Data submitted to CTFA reported the concentration of plant animals given 2000 mg/kg. One animal (male) in the high-dose
material in raw material as sold to the trade as 0.5% to 3% (CTFA group died on day 2, but all others recovered. No clinical signs
1999a). Concentration of use information stated that the maxi- were observed in animals given 500 mg/kg and there was no
mum concentration of Dioscorea Villosa (Wild Yam) Root Ex- mortality. Weight gain was not affected by exposure to either
tract used in body and hand creams, lotions, powders, and sprays dose level. Macroscopic examination of internal organs found
(excluding shaving preparations) was 0.00001% (0.000002% no abnormalities in any animal, including the one male in the
maximum solids from Wild Yam) and of the Extract used in high dose group that died on day 2 (CIT 2000b).
moisturizing creams, lotions, powders, and sprays was 15%
(0.5% maximum solids from Wild Yam) (CTFA 1999b).
Dioscorea Villosa (Wild Yam) Root Extract does not appear in Acute Dermal Toxicity
Annex II (list of substances which must not form part of the com- Dioscorea Villosa (Wild Yam) Root Extract (oleyl alcohol
position of cosmetic products) or Annex III (list of substances eluant) in corn oil was applied undiluted to the closely clipped
which cosmetic products must not contain except subject to the skin of five male (245 ± 4 g) and five female (216 ± 7 g) Sprague-
restrictions and conditions laid down) of the Cosmetics Direc- Dawley rats at a dose of 2000 mg/kg (CIT 2000c). The exposed
tive of the European Union (European Economic Community dorsum was covered with a semi-occlusive dressing for 24 h
2000). and the animals were observed for two weeks. Animals were
Dioscorea Villosa (Wild Yam) Root Extract is not included in necropsied on day 15 and a macroscopic examination of internal
the list of Japanese cosmetic ingredients (Rempe and Santucci organs was made as described above. No effects were seen in
1997). the treated animals, except for a reduced weight gain in female
rats between day 1 and day 8 (compared to historical controls).
The weight gain between day 8 and 15 was not different from
Noncosmetic historical controls.
D. villosa is used in herbal medicine for treatment of rheu-
matic diseases, colic, inflammation of the colon, cramps, inter-
mittent claudication, menstrual cramps, and ovarian and uterine Short-Term Dermal Toxicity
pain (Polunin and Robbins 1992). D. villosa root is used in the The local tolerance after cutaneous applications of Dioscorea
preparation of steroids by the pharmaceutical industry. Villosa (Wild Yam) Root Extract (oleyl alcohol eluant) in corn oil
Wild yam root and wild yam extract are included as compo- for 7 days in Sprague-Dawley rats was determined (CIT 2000d).
nents in a patent for pharmaceutical compositions and methods Groups of five male (341 to 457 g) and five female (219 to 293 g)
for protecting and treating sun damaged skin. The patent states rats received either 0% (control), 1%, 3%, or 10% concentration
that wild yam contains glycoside saponins and diosgenins, which of the test material at a volume of 1 ml/kg/day. Protective collars
are hormonal precursors to cortical steroids that are stated to re- were worn after each application, for the duration of the exposure
duce pain. These materials are present in the composition at period (6 h on weekdays, 4 h on weekends). After the exposure
between 0.5% and 8% by weight (Murad 1998). period the area was washed with water and dried. Clinical signs,
body weight, food consumption, and macroscopic evaluation of
internal organs was performed as described above. Some desqua-
GENERAL BIOLOGY mation and very slight erythema were seen in some female an-
Published data on the absorption, distribution, metabolism, imals but in none of the males. No signs of systemic toxicity
and excretion of Dioscorea Villosa (Wild Yam) Root Extract were seen. The authors concluded that the test substance was
(normally included in this section) were not found. not irritating in male and practically not irritating in female rats.
A 4-week study was conducted by CIT (2000e) in which the
ANIMAL TOXICOLOGY closely clipped skin of Sprague-Dawley rats were exposed to
Dioscorea Villosa (Wild Yam) Root Extract (oleyl alcohol elu-
Acute Oral Toxicity ant) in corn oil. Groups of five male (343 to 374 g) and five female
CIT (2000b) reported results of a single dose of Dioscorea (211 to 262 g) rats received either 0% (control), 1%, 3%, or 10%
Villosa (Wild Yam) Root Extract (oleyl alcohol eluant) in corn concentration of the test material at a volume of 1 ml/kg/day for
oil delivered by gavage to five male (182 ± 13 g) and five female a period of 29 days on the entire clipped dorsum. Protective
(141 ± 6 g) Sprague-Dawley rats. Two dose levels were used: collars were worn after each application, for the duration of the
500 mg/kg and 2000 mg/kg (10 animals each). Historical con- exposure period (6 h on weekdays, 4 h on weekends). After
trols were available. Weight gain was monitored. Clinical signs the exposure period the area was washed with water and dried.
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52 COSMETIC INGREDIENT REVIEW

Clinical signs, including erythema and edema; body weight; Sensitization

food consumption; hematological parameters; urinalysis; and The potential of Dioscorea Villosa (Wild Yam) Root Extract
macroscopic and microscopic pathology of skin and major in- (oleyl alcohol eluant) to induce delayed contact hypersensitivity
ternal organs were recorded. No clinical signs, other than ef- was evaluated in Hartley Crl: (HA) BR guinea pigs (CIT 2000g).
fects on the skin, were observed. No differences between any Fifteen male (354 ± 18 g) and 15 female (347 ± 14 g) animals
exposure level and controls were seen in body weight and food were used. On days 1, 8, and 15 the treatment group of 20 animals
consumption, hematology (including blood chemistry profiles), received an application of the undiluted test substance to the
urinalysis, macroscopic, or microscopic examination of internal induction site which was held in place with a waterproof plaster
organs. Desquamation and a slight to well-defined erythema at (controls received only corn oil) for 6 h. After the last induction
the site of application was seen in both control and exposed an- and a rest period of 14 days, the vehicle and test substance (25%
imals; there was no relationship of severity/frequency of these w/w in corn oil) were applied to a site different from the site of
endpoints as a function of dose and the effects were attributed to induction and held in place with a waterproof plaster for 6 h.
individual animals reactions to the repeated clipping, washing, Little erythema was seen during induction and what was seen
and drying of the application site. did not appear cumulative. No sensitization was seen.

REPRODUCTIVE AND DEVELOPMENTAL TOXICITY

Dermal Irritation
In a study on the content and estrogen receptor of phytoestro-
CIT (2000f) evaluated the acute dermal irritation of 10%
gens in various foods, herbs, and spices, Zava, Dollbaum, and
Dioscorea Villosa (Wild Yam) Root Extract (oleyl alcohol elu-
Blen (1998) did not find estrogen receptor binding in the “herb”
ant) in corn oil applied in a single topical application to three
wild yam (Dioscorea villosa).
New Zealand white rabbits. A single topical application (0.5 ml)
Eagon et al. (1999) presented, in an abstract, results of an
was applied a gauze pad, which was held to the clipped flank
estrogen-binding assay and a reporter-gene assay. In the bind-
of each animal with a semiocclusive dressing. The exposed site
ing assay, an ethanol extract of wild yam roots, at the highest
was evaluated at 1, 24, 48, and 72 h for erythema and edema. In
concentration, did interact slightly with estrogen receptors. Dilu-
two animals, a very slight erythema developed but disappeared
tions did not interact. In the reporter-gene assay, there was a 3.3×
with time. In one animal, an initial well defined erythema faded
enhancement of reporter-gene product activity at the maximum
to a very slight erythema. No edema was seen. The authors con-
concentration, and there was a dose dependence (Eagon 2000).
cluded that a 10% dilution of the test material was non-irritating
The estrogenic activity of Dioscorea Villosa (Wild Yam) Root
to intact rabbit skin.
Extract (oleyl alcohol eluant) in corn oil was evaluated in a
The primary skin irritation index of Actiphyte of Mexican
uterotrophic assay in juvenile female rats (CIT 2000h). Twenty-
Yam concentrate SP60 was determined in New Zealand albino
two-day-old female Sprague-Dawley rats were divided into six
rabbits (Laboratoire de Recherche et D’Experimentation 1998).
groups of six animals and treated by gavage for 4 days. The corn
A single application of undiluted material (0.5 ml) was deposited
oil vehicle was given to one group, 17-α-ethynylestradiol (EE)
on each of two gauze patches; one was applied to an abraded area
and diethylstilbestrol (DES) were each used as positive con-
and the other to unabraded, healthy skin of five male and one
trols in a group, at 0.010 and 0.015 mg/kg day−1 , respectively.
female rabbits. The patches were removed at 24 h. Observations
The test material was given at doses of 50, 150, or 500 mg/kg
were carried out between 30 min and 1 h, 48 h, and 5 days
day−1 to the final three groups. Animals were killed on day
after removal of the dressing. Erythema and edema in intact and
5. In addition to uterine and vaginal parameters, a complete
abraded skin were evaluated at the first and second examinations
macroscopic examination of the abdominal cavity was made,
and used to calculate a primary skin irritancy index. The authors
focused on the reproductive tract. A microscopic examination
stated that the test material was in the “irritant” range. There
of the uterus and the vagina was done. Positive controls demon-
did not appear to be a difference in response between intact and
strated the expected vaginal epithelial cell hyperplasia and hy-
abraded skin.
perkeratosis and uterine lumen dilation, endometrial epithelial
cell hypertrophy/hyperplasia and myometrial hypertrophy. All
Ocular Irritation doses of the test material were well tolerated. No differences
Three male rabbits from the above test were used to evaluate from controls were noted in the uterus or vagina in animals re-
the ocular irritation potential of Actiphyte of Mexican Yam con- ceiving the test material, in sharp contrast to animals receiving
centrate SP60 (Laboratoire de Recherche et D’Experimentation EE and DES, which had clear evidence of estrogenic activity.
1998). Undiluted test substance (0.1 ml) was instilled into one
eye without washing. Evaluation of the conjunctiva, iris, and GENOTOXICITY
cornea were made at 1, 24, and 48 h. Although conjunctival A bacterial reverse mutation assay of Dioscorea Villosa
irritation persisted, effects on the iris and cornea had resolved (Wild Yam) Root Extract (oleyl alcohol eluant) diluted with
at 48 h. The authors stated that the ocular irritation was in the dimethylsulfoxide (DMSO) was conducted using Salmonella
“slightly irritant” range. typhimurium strains TA98, TA100, TA1535, TA1537, TA1538,
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DIOSCOREA VILLOSA (WILD YAM) 53

and TA102 with and without S9 metabolic activation (Phoenix SUMMARY

International 2000). Using the plate incorporation method, dose Dioscorea Villosa (Wild Yam) Root Extract, an extract of the
levels of 52, 164, 512, 1600, and 5000 μg/plate were used. A rhizomes of the wild yam, D. villosa, was reported in 1998 to
precipitate was noted at 164 μg/plate and above. Using the prein- be used in one body and hand preparation. Concentration of use
cubation method, dose levels of 5, 9, 16, 29, and 52 μg/plate were data submitted by industry reported that the maximum concen-
used. A precipitate was noted from 16 μg/plate upwards. Sodium tration of use of Dioscorea Villosa (Wild Yam) Root Extract in
azide was used as a positive control for TA100 and TA1535, 2- body and hand creams, lotion, powders, and sprays and in mois-
nitrofluorene was the positive control for TA98 and TA1538, turizing creams, lotions, powders, and sprays was 0.00001%
t-butyl hyperperoxide was the positive control for TA102, and and 15%, respectively (0.000002% and 0.5% maximum solids,
9-aminoacridine was the positive control for TA1537. In all respectively, from wild yam.) Wild yam (D. villosa), which is
metabolic activation studies, 2-aminoanthracene was the pos- used in herbal medicine, contains diosgenin, steroidal saponins,
itive control. DMSO alone served as the negative control. glycosides saponins, alkaloids, tannin, phytosterols, and starch.
All positive and negative controls produced the expected re- HPLC and GC techniques can be used to identify both the elu-
sults. Weak to moderate cytotoxicity was seen in strain TA1538 ants and the plant material in Dioscorea Villosa (Wild Yam) Root
in the preincubation series at test concentrations of 9 μg/plate Extract. Using a specified process of manufacture/production,
and above, but this was not seen with metabolic activation one manufacturer demonstrated the ability to produce a stable
or in any of the plate incorporation series tests. No increase extract with a narrow range of diosgenin content.
in revertants was seen with any of the strains at any test material The extract produced using this methodology was tested in
concentration in the absence of metabolic activation. There was a acute and short-term toxicity tests, dermal irritation tests, a sen-
statistically significant increase in TA1537 revertants (frameshift sitization test, an ocular irritation test, a rat uterotrophic assay,
mutation) at the 52 μg/plate in the plate incorporation series and genotoxicity tests.
compared to vehicle controls, but not in TA1538 or TA98 (also An acute oral toxicity test produced hypoactivity, piloerec-
frameshift mutations) or in any other strains. At the 52 μg/plate tion, and dyspnea and a death in one of ten rats at 2 g/kg using
level in the preincubation series, there was a decrease in the specified extract, but no toxicity in rats given 0.5 g/kg. A
the number of TA98 (frameshift) revertants when compared dermal toxicity test using the specified extract demonstrated no
to the vehicle control. The authors concluded that the test mate- acute toxicity in rats. Both a 7-day local tolerance test and a 28-
rial was not mutagenic in the bacterial reverse mutation assay. day dermal toxicity test in rats produced no significant adverse
Chromosome damage or damage to the mitotic apparatus was effects at the maximum tested concentration of 10%. A single
determined in the bone marrow micronucleus test (CIT 2000i). application of undiluted extract to the intact and abraded skin of
Sprague-Dawley rats (∼5 weeks old) were given two oral treat- rabbits produced sufficient irritation for the test material to be
ments of Dioscorea Villosa (Wild Yam) Root Extract (oleyl al- rated “irritant,” but a 10% dilution was not irritating.
cohol eluant) in corn oil at dose levels of 0, 500, 1000, and 2000 Undiluted extract was only mildly irritating to the conjuctiva
mg/kg separated by 24 h. A positive-control group received one of the eye. Irritation in the iris and cornea was mild and transient.
oral dose of cyclophosphamide at 15 mg/kg. A preliminary tox- Undiluted extract also was not irritating during the induction
icity test produced no adverse effects. Animals were killed 24 h phase of a guinea pig sensitization study. Challenge with a 25%
after the last treatment. Bone marrow smears were prepared and dilution did not elicit any sensitization.
the number of micronucleated polchromatic erythrocytes (MPE) The specified extract at concentrations up to 500 mg/kg/day
were determined in a standard count of 2000 polchromatic ery- did not have any estrogenic activity in the juvenile rat utero-
throcytes (PE). The polychromatic and normal erythrocyte (NE) trophic assay.
ratio was determined in a standard count of 1000 erythrocytes. Genotoxicity assays in bacterial and mammalian systems
The mean values of MPE and the PE/NE ratio were not statis- were negative, except that Ames test strain TA 1537 was positive
tically different from controls and all the data were consistent at one dose level using the plate incorporation method, but not
with historical controls. Cyclophosphamide produced the ex- using a preincubation method.
pected increase in MPE frequency.
DISCUSSION
CARCINOGENICITY In reviewing the additional data provided by one supplier, in-
Published data on the carcinogenicity of Dioscorea Villosa cluding safety test data on a well-characterized product, the CIR
(Wild Yam) Root Extract were not found. Expert Panel concluded that it is possible to produce an extract
from the rhizome of the Mexican wild yam plant that is safe
CLINICAL ASSESSMENT OF SAFETY for use in cosmetics. The technique of eluant extraction using
Published data on the irritation nor the sensitization potential solvents, precipitation of plant extract material, and resolubiliza-
of Dioscorea Villosa (Wild Yam) Root Extract were not found. tion in the original solvent described in this safety assessment
Anecdotal information on the use in herbal medicine was not can effectively produce a material that is mostly solvent, but
considered. which has a clearly identifiable plant component. The expected
 Distributed for Comment Only -- Do Not Cite or Quote

54 COSMETIC INGREDIENT REVIEW

upper limit of concentration of diosgenin, a plant phytosterol, Active Organics. 2000e. Characterization of Actiphyte Mexican Wild Yam Con-
by this method is 3.5%. Use of material extracted in this manner centrate Special in oleyl alcohol. Unpublished data submitted by CTFA.
24 pages.2
in safety tests demonstrated that Dioscorea Villosa (Wild Yam)
Centre Internationale de Toxicologie (CIT). 2000a. Ultraviolet spectrum. Un-
Root Extract is minimally irritating to the skin and eye, does not published data submitted by CTFA. 16 pages.2
present any systemic toxicity, does not have estrogenic activity, CIT. 2000b. Acute Oral toxicity in rats - fixed dose method. Unpublished data
and is not genotoxic. submitted by CTFA. 25 pages.2
Although the Panel recognizes that the concentration at which CIT. 2000c. Acute dermal toxicity in rats. Unpublished data submitted by CTFA.
the actual plant extract is used in cosmetic products is low, 22 pages.2
CIT. 2000d. Local tolerance after cutaneous applications for seven days in rats.
one of the primary safety concerns with this plant extract is Unpublished data submitted by CTFA. 88 pages.2
the possible metabolic/endocrine activity, e.g., estrogen-like or CIT. 2000e. Four-week toxicity study by cutaneous route in rats. Unpublished
progesterone-like activity as a result of the presence of small data submitted by CTFA. 225 pages.2
amounts of plant phytosterols such as diosgenin. Extracts pre- CIT. 2000f. Acute dermal irritation in rabbits. Unpublished data submitted by
pared as described in this safety assessment, with an upper CTFA. 15 pages.2
CIT. 2000g. Skin sensitization test in guinea pigs. Unpublished data submitted
limit of 3.5% diosgenin, did not have any estrogenic activity, by CTFA. 28 pages.2
demonstrating that it is possible to produce material that does CIT. 2000h. Study for estrogenic activity by oral route (gavage) in juvenile
not present this specific safety concern. female rats (uterotrophic assay). Unpublished data submitted by CTFA.
Concern, however, was expressed about alternative appro- 132 pages.2
aches to extraction that might not produce material with the CIT. 2000i. Bone marrow micronucleus test by oral route in rats. Unpublished
data submitted by CTFA. 35 pages.2
same safety profile described in this safety assessment, espe- Cosmetic Ingredient Review (CIR). 1999. Final report on the safety assessment
cially if pesticides were used on the plants. Although extracts of Wild Yam (Dioscorea Villosa) Extract. Washington, DC: CIR.
from pesticide-free plants were not considered genotoxic and Cosmetic, Toiletry, and Fragrance Association (CTFA). 1999a. Botanical
there do not appear to be any components that could be carcino- Cosmetic Ingredient Description for Dioscorea Villosa (Wild Yam) Root Ex-
genic, pesticide residues could raise this issue. The Panel urged tract. Dated June 28. Unpublished data submitted by CTFA. 2 pages.2
CTFA. 1999b. Product type and concentration of use for Dioscorea Villosa (Wild
that manufacturers limit pesticide residues to the limit previ- Yam) Root Extract. Dated July 19. Unpublished data submitted by CTFA.
ously used for lanolin of not more than 40 ppm (with not more 1 page.2
than 10 ppm for any one residue). CTFA. 2000. Letter to CTFA from Active Organics. Unpublished data submitted
The conclusion regarding safety is valid only for extracts by CTFA. 1 page.2
prepared in a manner that produces a similar chemical profile as Eagon, P. K. 2000. Personal communication to Alan Andersen.2
Eagon, P. K., N. B. Tress, H. A. Ayer, J. M. Wiese, T. Henderson, M. S. Elm,
that described in this report, particularly as regards diosgenin. and C. L. Eagon. 1999. Medicinal botanicals with hormonal activity. In Pro-
Prepared in this manner, the Panel’s conclusion is that these ceedings of the American Association for Cancer Research Annual Meeting
extracts do not have significant estrogenic activity. Extracts not 40:161–162.
prepared in a manner that produces a similar chemical profile European Economic Community. 2000. Cosmetics Directive of the European
would be considered safe if they have a similar safety test profile. Union. Updated version—Incorporating all amendments until August 1, 1995.
Dir. 76/768/EEC.
Food and Drug Administration (FDA). 1998. Frequency of use of cosmetic
ingredients. FDA database. Washington, DC: FDA.
CONCLUSION Laboratorie de Recherche et D’Experimentation. 1998. Determination of pri-
On the basis of the chemical and animal data included in mary skin irritation index and eye irritation index in the rabbit. Unpublished
this safety assessment, the CIR Expert Panel concludes that data submitted by CTFA. 16 pages.2
Dioscorea Villosa (Wild Yam) Root Extract is safe for use in Mowrey, D. B. 1986. The scientific validation of herbal medicine, 111–112.
New Canaan, CT: Keats Publishing, Inc.
cosmetic products.
Murad, H. 1998. U.S. Patent (5,804,168) for pharmaceuticals, compositions,
and methods for protecting and treating sun damaged skin. http://www.
uspto.gov/patft/index.html
REFERENCES Ody, P. 1993. The complete medicinal herbal, 52. New York, NY: DK Publishing,
Active Organics. 2000a. Preparation of Wild Yam Extract and analysis of dios- Inc.
genin (HPLC method). Unpublished data submitted by CTFA. 8 pages.2 Pepe, R. C., J. A. Wenninger, and G. N. McEwen, Jr, eds. 2000. Interna-
Active Organics. 2000b. Product specification, composition statement, certifi- tional cosmetic ingredient dictionary and handbook, 8th ed., vol. 1, 462.
cate of analysis, and material safety data sheet for hexyldecanol extract. Un- Washington, DC: CTFA.
published data submitted by CTFA. 10 pages.2 Phoenix International. 2000. Bacterial reverse mutation test. Unpublished data
Active Organics. 2000c. Product specification, composition statement, certifi- submitted by CTFA. 104 pages.2
cate of analysis on material used in safety tests and material safety data sheet. Polunin, M., and C. Robbins. 1992. The natural pharmacy. An illustrated guide
Unpublished data submitted by CTFA. 9 pages.2 to natural medicine, 48, 99. New York: Macmillan Publishing Co.
Active Organics. 2000d. Characterization of Actiphyte Mexican Wild Yam Rempe, J. M., and L. G. Santucci. 1997. CTFA List of Japanese Cosmetic In-
Concentrate Special in hexyldecanol. Unpublished data submitted by CTFA. gredients, 3rd ed., Washington, DC: CTFA.
15 pages. Ritchason, J. 1995. The little herb encyclopedia, 3rd ed., 248–249. Utah:
Woodland Health Books.
Zava, D. T., C. M. Dollbaum, and M. Blen. 1998. Estrogen and pregestin
2 Available for review: Director, Cosmetic Ingredient Review, 1101 17th bioactivity of foods, herbs, and spices. Proc. Soc. Exp. Biol. Med. 217:369–
Street, NW, Suite 310, Washington, DC 20036, USA. 378.