JOURNAL OF THE AMERICAN COLLEGE OF TOXICOLOGY

Volume 5, Number 5, 1986

Mary Ann Liebert, Inc., Publishers

Final Report on the Safety

Assessment of Glyceryl Oleate

Glyceryl Oleate, the glyceryl 1-monoester of oleic acid, is used in cosmetic

products as an emulsifier at concentrations up to 5%.
Oral administration of a single 13 ml/kg dose of a sunscreen formulation
containing 5% Glyceryl Oleate to rats produced no signs of toxicity and no
lethality.
A single exposure of undiluted Clyceryl Oleate in animal dermal irritation
studies produced only minimal irritation. Daily applicatoins of 25.0% corn oil
solution of a formulation containing Glyceryl Oleate for 20 days produced se-
vere dermal irritation in rabbits. In a 4-week dermal toxicity/phototoxicity
study, product formulations containing up to 5% Glyceryl Oleate produced
slight reversible dermal irritation. Subchronic and chronic toxicity data from
studies with animals and humans that were used in the safety assessment of
glycerides, glycerol, oleic acid, and sodium oleate are presented.
Minimal to moderate eye irritation was produced by undiluted Glyceryl
Oleate in rabbits.
Glyceryl Oleate administration was associated with development of a
small number of brain tumors in a two-generation study in mice. Digestive
tract tumors were found in mide fed 200 mg/mouse per day Clyceryl Oleate
for four-seven generations. The results of these studies were considered equiv-
ocal. Doses of 1.5 and 6.0 mg/mouse per day of Glyceryl Oleate in saline in-
creased the survival period of mice with implanted Ehrlich ascites tumors; the
higher dose inhibited tumor growth.
Formulations containing 5% Glyceryl Oleate were nonirritating in a hu-
man cumulative occlusive patch test and in repeat insult patch testing at 15%.
Glyceryl Oleate in formulations is not phototoxic.
It is concluded that Glyceryl Oleate is safe as a cosmetic ingredient in the
present practices of use and concentration.

CHEMISTRY

Chemical and Physical Properties

lyceryl Oleate (CAS 11 l-03-5; 25496-72-4) is the glyceryl 1-monoester of
oleic acid (cis-9-octadecenoic acid). The structural formula of Glyceryl Ole-
ate is as follows(‘+

391
 392 COSMETIC INGREDIENT REVIEW

CH2OH

Glyceryl Oleate occurs as off-white to yellow flakes or as a soft semisolid. It

is dispersible in water and soluble in acetone, methanol, ethanol, cottonseed oil,
and mineral oil.(‘) Glyceryl Oleate is also known as Monoolein, Glyceryl Mono-
oleate, and Glycerol Monooleate.
A summary of the properties of Glyceryl Oleate appears in Table 1. In addi-
tion, the emulsifying and physicochemical properties of several monoglycerides
have been measured in a Russian study.t3’

TABLE 1. Chemical and Physical

Properties’z.p.‘O)

Clyceryl Oleate

Molecular weight 365.55

Melting point (“C) 35

Boiling point (“C) 238-240

Density 0.9420

Acid value 5 max

Saponification value 155-l 70

Iodine value 48-80

Analytical Methods
Gas chromatography has been used to isolate and identify monoglycerides
(via comparison with standard retention values).(4) Several other procedures
have been coupled with gas chromatography for the determination of the sepa-
rated monoglycerides or their hydrolysis products (hydrolysis products of Glyc-
eryl Oleate are glycerol and oleic acids). These methods are nuclear magnetic
resonance spectrometryC5) and a battery of spectrophotometric analyses. The
most widely used chemical assay for the quantitation of glycerol or its l-mono-
glycerides involves periodate or lead tetraacetate oxidation of these compounds’
primary alcohol groups.(6,7) Qualitative chemical tests to assay for the presence
of glycerol involve formation of colored derivatives.(4*6) Infrared spectrometry
may also be used for functional group identification or for fingerprinting upon
comparison with stock standards.“)
ASSESSMENT: GLYCERYL OLEATE 393

Method of Manufacture

“Monoglycerides do not occur naturally in appreciable quantities, except in

fats and oils that have undergone partial hydrolysis.““) The most important
method of monoglyceride preparation is the glycerolysis of fats and oils. De-
pending on the molar ratios of the reactants, this transesterification reaction can
yield product mixtures containing varying quantities of monoglycerides, com-
mercially noted as “40 percent monos” and “60 percent monos.“(”
Separation of the monoglycerides from di- and triglycerides is usually
achieved by molecular distillation of the glycerolysis product mixture, resulting
in the “90 percent mono” mixture used by the cosmetic industry. These commer-
cial 90% monoglyceride mixtures predominantly consist of cx-monoglycerides;
fi-monoglycerides are present in smaller quantities. lsomerization of P-mono-
glycerides to the more stable a-isomers occurs readily.“’
The Glyceryl Oleate used by the cosmetic industry may be manufactured by
the glycerolysis (glycerol is normally obtained from the triglycerides of oil and
fats) (8) of oils containing high concentrations of oleic acid: olive oil (80% oleic
acid), peanut oil (60% oleic acid), teaseed oil (85% oleic acid), or pecan oil (85%
oleic acid). The Glyceryl Oleate could then be distilled from the resulting prod-
uct mixture (vapor pressure of Glyceryl Oleate at 186°C is 0.2 mm).(‘)

Impurities

Glyceryl Oleate used by the cosmetic industry is a mixture of monoglycer-

ides consisting mainly of the compound, glyceryl cr-monooleate.(2) The stated
90% minimum monoester content as written includes both (Y- and fl-monoglyc-
erides of oleic acid and glycerol and may also include glycerol monoesters con-
taining other fatty acids depending on the method of manufacture (e.g., sources
of reactants).
Constituents, such as free fatty acids and glycerol, may also exist in the Glyc-
eryl Oleate preparation at maximal concentrations of 2.5% and l.O%, respec-
tively.“)

USE

Purpose, Scope, and Extent of Use in Cosmetics

Glyceryl Oleate is used primarily as an emulsifier in cosmetic products. It

has been reported to the Food and Drug Administration (FDA) that Glyceryl Ole-
ate is an ingredient in 716 cosmetic formulations. Reported concentrations
ranged from 10.1% to 5%. The concentrations of Glyceryl Oleate in 455 of the
716 cosmetic formulations were not reported to FDA. Cosmetic formulations
containing Glyceryl Oleate are predominantly lipsticks, eye shadows, makeup
bases, and skin care preparations.‘“)
The cosmetic product formulation listing that is made available by FDA is
compiled through voluntary filing of such data in accordance with Title 21 part
720.4 of the Code of Federal Regulations. (12) Ingredients are listed in preset con-
centration ranges under specific product type categories. Since certain cosmetic
394 COSMETIC INGREDIENT REVIEW

ingredients are supplied by the manufacturer at less than 100% concentration,

the value reported by the cosmetic formulator may not necessarily reflect the ac-
tual concentration found in the finished product; the actual concentration in
such a case would be a fraction of that reported to the FDA. Data submitted
within the framework of preset concentration ranges provide the opportunity for
overestimation of the actual concentration of an ingredient in a particular prod-
uct. An entry at the lowest end of a concentration range is considered the same
as one entered at the highest end of that range, thus introducing the possibility of
a two- to ten-fold error in the assumed ingredient concentration. See Table 2 for
a list of cosmetic products containing Glyceryl Oleate.

Surfaces, Frequency, and Duration of Contact

Cosmetics containing these ingredients are applied to all areas of the skin
and mucous membranes. These cosmetics are frequently applied to the face and
have the potential for contacting the eye or being ingested from the lips. Prod-
ucts containing these ingredients are applied up to several times a day and can
remain in contact with the skin for long periods of time.

Noncosmetic Use
Monoglycerides consisting of a mixture of glyceryl mono- and diesters, and
minor amounts of triesters, that are prepared from fats or oils or fat-forming acids
derived from edible sources(‘3) are affirmed as generally recognized as safe
(GRAS) substances (21 CFR 182.4505, 182.90)(12) and indirect food additives (21
CFR 175.105, 176.210)(12) for human consumption without restriction on their
concentration (at concentrations not to exceed good manufacturing practice,
GMP). Federal regulations allow the use of Glyceryl Oleate as a prior-sanctioned
food ingredient (21 CFR 181 .27)(12) and as both an indirect (21 CFR 175.300,
1 75.320)‘12’ and direct (21 CFR 172.515) (W food additive. These regulatory deci-
sions were based on a review of data in the following areas: subchronic(14-16)
and chronic (multigeneration reproduction) (I’) feeding studies using Glyceryl
Oleate or monoglyceride mixtures derived from oils; subchronic(l*~lg) and
chronic(20) feeding studies of similar glycerides; studies on the absorption and
storage of Glyceryl Oleate and other monoglycerides(‘7~18.2’~; and the well-docu-
mented metabolic fate of glycerides in the human body. Studies on the metabo-
lites of Glyceryl Oleate, glycerol, and oleic acid as they appear in reviews used
by the FDA in the regulation of glycerol, glycerides, and oleic acid are summa-
rized in this report.
The FDA proposed affirmation of GRAS status of Glyceryl Oleate (Proposed
issuance of 21 CFR 184.1323) and monoglycerides (proposed issuance of 21 CFR
184.1505) for several additional purposes in human food and concurrent dele-
tion of its listing as a direct food additive (amendment of 21 CFR 172.515).(“)
The listing of the most prevalent fatty acids occurring in monoglycerides in
Section 184.1505 included oleic acid.(13)
Glyceryl Oleate is used by the pharmaceutical industry as a carrier com-
pound, (23) in mixed micellar form with bile salts for the enhancement of intesti-
nal drug absorption,(24) and for the encapsulation and/or solubilization of partic-
TABLE 2. Product Formulation Data”‘)
%
z
No. of product formulations within each concentration range (%j z
Total no. of Total no. 3
formulations containing Unreported
Product category in category ingredient concentration >25-50 > IO-25 >5-10 >l-5 >o. I-l 10.7 z
ii
Clyceryl Oleate

Baby lotions, oils, powders, and 56 3

creams
Other bath preparations 132 1 1 - - - - -
Eye shadow 2582 26 15 - 1
Mascara 397 3 - - 3
Other eye makeup preparations 230 2 1 - - 1
Hair conditioners 478 5 3 - - - 2
Hair shampoos (noncoloring) 909 2 1 - - 1
Tonics, dressings, and other hair 290 1 - - - - - 1
grooming aids
Blushers (all types) 819 9 a - 1
Makeup foundations 740 8 8 - - - -
Lipstick 3319 570 355 - - - 215
Makeup bases 831 25 24 - - - - - 1
Rouges 211 2 2 - - - -
Other makeup preparations (not eye) 530 7 - - - - 7
Skin cleansing preparations (cold 680 8 5, - - 1 1 1
creams, lotions, liquids, and pads)
Face, body, and hand skin care prep 832 12 9 - - 2 - 1
arations (excluding shaving prepa-
rations)
Hormone skin care preparations 10 1 - - - - - - 1
Moisturizing skin care preparations 747 14 7 - - - 3 3 1
Night skin care preparations 219 5 2 - - - 1 2 -
Paste masks (mud packs) 171 1 - - - - - - 1
Wrinkle smoothers (removers) 38 1 1 - - - - - -
Suntan gels, creams, and liquids 164 7 7 - -
Other suntan preparations 28 3 3

1981 TOTALS 716 455 0 0 0 18 10 233

396 COSMETIC INGREDIENT REVIEW

ular drugs.(‘+“) Glyceryl Oleate is often used in controlled studies on the phys-
iology and biophysics of laboratory-constructed lipid membranes.(*‘) The use of
Glyceryl Oleate as a fusogen in heterokaryon formation is reported for the study
of cell differentiation and genetics.(29)

BIOLOGY

Absorption, Distribution, and Metabolism

Monoglycerides are metabolized by the same mechanisms as are the triglyc-
erides of the diet t30) Their digestion, intestinal absorption, and transport have
been reviewed. (3’-37)
The catabolic fate of the glycerol and fatty acid components of glycerides is
well documented.(3s.37-39) Glycerol, phosphorylated and oxidized, enters the
glycolytic pathway as dihydroxyacetone phosphate, and fatty acids primarily un-
dergo fl-oxidative degradation to form acetyl-CoA.
Oleic acid, a monoenoic acid, requires an isomerase after partial cleavage to
catalyze the isomerization and shifting of the cis double bond before P-oxidation
continues. Oleic Acid is currently being reviewed by Cosmetic Ingredient
Review. (40)
The monoglyceride, Glyceryl Oleate, as well as its components, glycerol and
oleic acid, are common intermediates in both lipid oxidation and synthesis.

General Effects

Addition of 1 mM Glyceryl Oleate plus 3 mM oleic acid to an incubation of

the conjugated bile salt, sodium taurodeoxycholate, with segments of everted
jejunal intestine from Sprague-Dawley rats diminished the tissue’s permeability
observed with the bile salt alone. (41) The mixture also prevented changes in the
gross appearance of the intestinal mucosa that were found with the bile salt
alone.
Weanling rats were fed a diet of 25% tristearin supplemented with 5% Glyc-
eryl Oleate or with 2.5% Glyceryl Oleate plus 2.5% oleic acid. The absorption of
tristearin, calcium, magnesium, and phosphorus was not altered.t4*)
The presence of Glyceryl Oleate within the intestinal lumen enhanced the
intestinal absorption of macromolecules. Glyceryl Oleate-bile salt mixed micel-
lar solutions were necessary adjuvants to potentiate heparin absorption.(43-44)
The use of Glyceryl Oleate as a micelle promoter in chickens alleviated the
toxic effects of T-2 toxin, a secondary metabolite of several species of the genus
fusarium.(45) Mixed micellar solutions containing taurocholate and Glyceryl
Oleate prevented deoxycholate-induced malabsorption in the rat jejunum.(46)
Micellar fat containing Glyceryl Oleate decreased the contractility of canine
gastric muscles after stimulation with acetylcholine or 5-hydroxytryptophan.(47)
A volume of 10 ml of micellar fat consisting of 0.25 mM Glyceryl Oleate, 0.5 mM
oleic acid, and dog bile diluted by a salt solution was instilled into the duodena
of dogs following intravenous injections of the following gastric stimuli: food,
acetylcholine, or 5hydroxytryptophan. Bile alone and saline did not produce
these responses.
ASSESSMENT: CLYCERYL OLEATE 397

Glyceryl Oleate was a minor component (1.3%-6.7%) in Fruend water-in-oil

adjuvant mixtures that were used to sensitize mice to a protein antigen. Al-
though the protein in emulsions containing Glyceryl Oleate succeeded in pro-
ducing Arthus reactions and delayed hypersensitivies, no conclusion could be
reached on the potential adjuvant properties of Glyceryl Oleate as an individual
ingredient.(48)
Inhibition of cow’s milk lipoprotein lipase by a human plasma apolipopro-
tein was reversed by the addition of Glyceryl Oleate to the reaction mixture.(49)
The addition of Glyceryl Oleate (1 w/v %) to a culture of the fungus, Candida
paralipolytica, increased the lipase activity. tso) The free fatty acids tested did not
significantly increase Iipase activity over controls.
Glyceryl Oleate prevented the fusion of chicken myoblasts in vitro at con-
centrations ranging from 40 to 70 &ml under conditions that have been re-
ported for erythrocytic fusion. (51) Concentrations above 80 pg/ml were toxic to
the myoblastic cultures.
The interaction of fusogenic lipids, such as Glyceryl Oleate, with erythrocyte
ghosts was studied using fluorescence probes. (52) Changes in the quantum yield,
fluorescence intensity, and emission wavelength of the probe in the presence of
Glyceryl Oleate were due to the production of a less ordered, functionally fluid
membrane structure. The chemically related nonfusogenic lipid, glyceryl mono-
stearate, had no effect on the observed fluorescence parameters.
The ability of Glyceryl Oleate to inhibit the antimicrobial activity of two im-
idazole antimycotic drugs against Candida was evaluated using an agar diffusion
procedure. (53) Glyceryl Oleate decreased the diameter of the inhibition zone at
a concentration of 0.25 mM. No decrease was observed at the lower concentra-
tions of 0.13 mM and 0.06 mM.
The antimicrobial activity of Glyceryl Oleate and other polyhydric alcohols
was assessed.(54) Glyceryl Oleate had slight activity, causing inhibition of growth
of Corynebacterium sp. at concentrations above 1.40 pmol/ml. Other microorga-
nisms, such as Streptococcus pyogenes, Nocardia asteroides, and Staphylococcus
aureus, were not inhibited up to the highest concentration tested, 2.81 pmol/ml.
Glyceryl Oleate induced aggregation of nematodes (Bursaphelenchus ligni-
co/us) as compared with untreated controIs.(55)

ANIMAL TOXICOLOGY

Acute Oral Toxicity

A sunscreen formulation containing Glyceryl Oleate (at 5%) was evaluated
for acute toxicity upon oral administration to 10 Fischer rats.(s6) After a 14day
observation period for signs of toxicity, the study directors concluded that the
single 13 ml/kg dose was not lethal in rats.

Skin Irritation
Five studies using the single insult occlusive patch test were performed to
evaluate the primary dermal irritation potential of Glyceryl Oleate at two con-
centrations.(57-“‘) A volume of 0.5 ml was placed on the clipped dorsal skin of
398 COSMETIC INGREDIENT REVIEW

nine rabbits. Sites were graded for erythema and edema 2 and 24 h after expo-
sure (maximum score for either erythema or edema = 4). In the three studies
with undiluted Glyceryl Oleate, it was concluded that it had minimal skin irrita-
tion potential; erythema scores ranged from 0.5 to 1 .(57+9) Similar results and
conclusions were reported in the two studies using 50% Glyceryl Oleate in corn
oil(60-61) (Table 3).
The dermal toxicity of a sunscreen formulation containing 5% Glyceryl Ole-
ate was evaluated using three New Zealand White (NZW) rabbits.(56) Volumes of
0.5 ml were applied to the animals’ clipped dorsal skin once daily for 4 days.
After a 7-day assessment period for dermal irritation, which was characterized by
well-defined to moderate erythema, slight edema, and subsequent slight desqua-
mation, the resultant irritation index was 3.0 (max = 8.0) (Table 3).

Ocular Irritation

Glyceryl Oleate was evaluated for ocular irritation in six rabbits using the
Draize Eye Test. Undiluted and 50.0% in corn oil preparations were adminis-
tered at a volume of 0.1 ml. The Draize system,(62) which has a calculated maxi-

TABLE 3. Primary Skin Irritation and Dermal Toxicity of Glyceryl Oleate

No. of
Material tested rabbits Method Conclusion Reference

Glyceryl Oleate undiluted SIPTa-occlusive Minimal skin irritation 57

PIP = 0.72

Glyceryl Oleate undiluted SIPT-occlusive Minimal skin irritation 58

PII = 0.67

Clyceryl Oleate undiluted SIPT-octilusive Minimal skin irritation 59

PII = 0.67

Clyceryl Oleate 50% in corn SIPT-o’cclusive Minimal skin irritation 60

oil PII = 1.00

Glyceryl Oleate 50% in corn SIPT-occlusive Practically nonexistent 61

oil skin irritation
PII = 0.33

Clyceryl Oleate 5% in sun- Dermal toxicity of 0.5 Mild dermal irritation 56

screen formulation ml applied to clipped PII = 3.0
dorsal skin once daily
for 4 days

Glyceryl Oleate at unspecified Subchronic dermal Severe irritation at ap- 66

concentration in cosmetic toxicity (28 days). plication site of
formulation 25.0% wlv formula- treated rabbits; gross
tion in corn oil ap- and microscopic al-
plied to shaved terations noted
abraded and intact
skin 5 days per week
for 4 weeks

aSIPT, single insult patch test.

bPll, primary irritation index. Maximum possible scbre = 8.00.
ASSESSMENT: CLYCERYL OLEATE 399

mum irritation score of 110, was used to score the extent of irritation. In the two
studies using undiluted Glyceryl Oleate, results were similar after 2 days of ob-
servation; mean scores were 0 and 1 in 110. Glyceryl Oleate produced minimal
eye irritation. (63*64)The 50.0% Glyceryl Oleate preparation was also minimally ir-
ritating, and the mean scores were 1 and 2 for Days 1 and 2, respectively(65)
(Table 4).
A fragrance preparation containing Glyceryl Oleate at 19.0% concentration
was tested in rabbits with the standard Draize Test. The total mean score of 12
on Day 1 decreased to 8 on Day 2, 6 on Day 4, and 2 on Day 7. Individual mean
scores for two of the six rabbits tested were in the 25 to 35 range on the first day,
decreasing to approximately 18 by Day 4 and to 7 by Day 7. All other rabbits had
negative to transient minimal responses. The formulation produced moderate
eye irritationt6’) (Table 4).
A 0.1 ml volume of a sunscreen formulation containing 5% Glyceryl Oleate
was evaluated for eye irritation in six NZW rabbits.(56) Scoring was performed 1
h after treatment and on Days 1, 2, 3, and 7. Slight conjunctivitis was observed
after 1 h, clearing within 24 h, and no signs of irritation to other tissues were
noted (Table 4).

Su bchronic Dermal Toxicity and Phototoxicity

A 28-day subchronic dermal toxicity study assessed the safety of a cosmetic

formulation containing Glyceryl Oleate (at an unspecified concentration) in 10
albino rabbits.r@j) A 25.0% (w/v) solution of the formulation in corn oil was ap-
plied to shaved skin that had been either abraded or left intact. The 2.0 ml/kg

TABLE 4. Ocular Irritation of Clyceryi Oleate

No. of
Material tested rabbits Results Reference a

Glyceryl Oleate undiluted 6 Minimal eye irritation; 63

mean score = 1 (max
score = 110) on Day
1 following treatment

Glyceryl Oleate undiluted 6 Minimal eye irritation; 64

mean score = 1 on
Day 1

Glyceryl Oleate 50% in 6 Minimal eye irritation; 65

corn oil mean score = 1 on
Day 1

Clyceryl Oleate 19.0% in 6 Moderate eye irritation; 67

fragrance preparation mean score = 12 on
Day 1, 8 on Days 2
and 3, 6 on Day 4, 2
on Day 7

Clyceryl Oleate 5% in 6 Slight conjunctivitis 1 h 56

sunscreen formulation after treatment;
cleared within 24 h

aAll studies followed methods of Draize.(6*)

400 COSMETIC INGREDIENT REVIEW

dose was left in contact with the skin for an indefinite period of time. The rabbits
were treated 5 days per week for a period of 4 weeks. The major response to re-
peated administration of this formulation was “severe irritation” of the skin at the
site of application. Alterations included erythema, severe edema, and desqua-
mation, fissures, hemorrhages, and pustules. Microscopic changes included
acanthosis, hyperkeratosis, focal epidermal ulceration, focal dermal inflamma-
tion, abscess formation, and/or focal escharosis at some of the treated sites. No
skin reactions were noted in controls. Other results (e.g., mortality, gross beha-
vior/appearance, and results of hematological, clinical chemistry, and urine
analyses) were negative or not treatment-related (Table 3).
Three formulations containing two sunscreen ingredients (maximum con-
centrations 2.0% and 4.0%) were evaluated in a 28-day subchronic dermal tox-
icity/phototoxicity study in NZW rabbits. (68) The sunscreens contained Glyceryl
Oleate at a 5% concentration. Topical applications of 6 mg cream per cm2 to
clipped dorsal intact and abraded skin sites of the animals (four animals per
group) were followed by a 4-minute exposure (at one-half the minimum ery-
themal dose) to UV radiation (Westinghouse FS-20 sunlamp) and a 6-h occlusion
of the test sites. This treatment was repeated 5 days each week followed by 2
nontreatment days for 4 weeks. Animals were then observed for 2 weeks before
necropsy. The four deaths (one control, three treated) were reportedly due to
naturally occurring chronic enteritis. Body weights, mean group feed consump-
tion, and hematological and urinalysis data from treated animals reflected nor-
mal variability. The organ:body weight disparity of some treated animals with
controls was not considered toxicologically significant. All three formulations
caused slight dermal irritation during the first week of treatment that was similar
to that observed in several control animals exposed to UV light alone. Maximal
irritation during the second week, which was sustained through the remainder
of the treatment period, was characterized by slight to moderate erythema, slight
edema, and scaly desquamation. The severity of dermal irritation was equivalent
at both abraded and intact sites. Normal healing occurred during the 2-week ob-
servation period following treatment.

Subchronic and Chronic Toxicity of Glycerol and Oleic Acid

Toxicological data on glycerol and oleic acid, metabolic products of Glyc-

eryl Oleate, were obtained from subchronic and chronic ingestion studies used
to regulate these GRAS substances.(30.6g-73)

Subchronic Oral Toxicity of Glycerol

Rats fed glycerol at concentrations up to 20% in their diets or by stomach
tube for periods of 4-11 weeks had no adverse effects that could be attributed to
glycerol consumption. (74-7g)Criteria such as body weight gain, food and water
intake, resistance to cold, mortality, behavior, blood chemistry, hematology,
and gross and microscopic features of major internal organs and tissues, were
observed.
Oral doses of up to 3 g of undiluted glycerol given three times per day for a
total of eight doses resulted in hyperemia, petechial hemorrhages, and erosion
of the gastrointestinal mucosa of rats and dogs.(80)
ASSESSMENT: GLYCERYL OLEATE 401

Volumes greater than 5 ml of a 50% aqueous saline solution of glycerol ad-

ministered to guinea pigs by stomach tube or from a drinking cup daily for a
period of 30-40 days produced signs of acute toxicity and death.‘“‘) Doses of 10
ml of the 50% solution for 30-40 days were well tolerated by rabbits.(6’) The red
blood cell count of the treated guinea pigs had decreased. No gross pathological
changes and no glycerol-related changes in plasma or erythrocytic cholesterol
concentrations were found in either species.
Three-month administration of up to 20% solutions of glycerol to rats as
drinking water resulted in the death of 2112 rats receiving the highest concentra-
tion and temporary impairment in the development of the remaining rats.(“)
Growth of rats was normal at concentrations of glycerol of less than or equal to
10%. Temporary growth impairment was observed in rats administered 20%
glycerol solutions for 3 months.(82)
After the oral administration of 2.0 ml/kg doses of glycerol to two dogs twice
weekly for 4 months, growth was normal and no abnormalities were found in
urine and the internal organs.(83’
The feeding of glycerol to rats at concentrations up to 41 O/O (as a dietary sup-
plement) for 21-25 weeks did not produce changes in growth or in the liver, kid-
neys, or intestines of these animals. (74) In another study, subnormal growth was
found in rats fed diets containing greater than 30% glycerol for 20 weeks.(*4)
Pathological changes were observed in rats fed diets containing glycerol at con-
centrations greater than 10%. The most marked changes were hydropic and fatty
changes of hepatocytes.

Subchronic Dermal Toxicity of Glycerol

Doses of 0.5-4.0 ml (0.6-5 g) per kg natural or synthetic glycerol were ap-
plied to the shaved dorsal skin of 24 albino rabbits for an 8-h exposure, 5 days
per week, for 18 weeks. (85) No evidence of skin irritation was observed; no ab-
normalities were found in urine or blood or after gross and microscopic exami-
nations of internal organs.

Chronic Oral Toxicity of Glycerol

The only untoward effect in a 6-month study of rats given 5% solutions of
either synthetic or natural glycerol as drinking water was calcified masses in the
renal tubules of 6110 rats.(86) Administration of 1 .O ml/kg of a 50% aqueous glyc-
erol solution to 60 rats for 6 months had no adverse effects on development, sur-
vival, internal organs, skeletal system, or hepatic glycogen.(“)
Three dogs fed glycerol at a concentration of 35% (as a dietary supplement)
for 31 weeks had normal growth. (74) In the 1Cweek period following a reduc-
tion in feed consumption, treated dogs lost an average of 16% of their previously
attained weight; control dogs maintained their weight. Diuresis was observed in
treated dogs, but no hemoglobinuria, albuminuria, liver degeneration, or gross
or microscopic abnormalities of internal organs were found.
Growth impairment, reduced activity, and dull coats were observed in rats
fed 61% glycerol substituted for starch for 40 weeks. These changes were consid-
ered due to a lack of starch rather than to glycerol toxicity. Rats fed 20% and
40% glycerol diets for 40 weeks had normal growth.(74)
402 COSMETIC INGREDIENT REVIEW

In 2-year toxicity studies using rats and dogs fed 0, 5, 10, and 20% glycerol,
no treatment-related adverse effects were found.(85.87) Although Hine et al.(“)
observed high incidences of albuminuria and glycosuria in treated rats and high
liver:body weight ratios in females fed diets with 20% glycerol, they concluded
that glycerol at concentrations below 20% would not cause untoward effects in
rats.

Subchronic Oral Toxicity of Oleic Acid

A volume of 10 ml of oleic acid (approximate dose 2 g/kg) administered to
four albino rabbits by stomach tube every other day for 4 days resulted in the
death of one of the four rabbits. (W Other signs included hair loss and seborrheic
lesions on the rabbits’ ears. No adverse effects were observed after administra-
tion of a volume of 2.5 ml (approximate dose 0.6 g/kg).
Feeding of a 5% oleic acid diet (approximate dose 6 g/kg daily) to chicks for
4 weeks had no adverse effect.(8g)

Chronic Toxicity of Oleic Acid

The growth rates of albino mice receiving weekly subcutaneous injections of
0.25 ml and 0.5 ml of a 5% oleic acid emulsion (approximate dose 12-15 g/kg)
for 15 months were normal.
Rats fed a 15% Oleic Acid diet for 5 months had normal development and
good general [Link]) A progressive reduction in spermatogenesis and pro-
longed estrus cycles (although most females bore living young) were noted;
these signs were considered typical of animals fed diets deficient in essential fatty
acids.

Carcinogenicity

Several egg lipids were examined for their potential to produce brain tumors
in mice of the T.M. strain.‘g2) Purina mice chow, which was fed to controls ad
libitum, corn oil, cholesterol, Glyceryl Oleate, corn oil plus cholesterol, or Glyc-
eryl Oleate plus cholesterol were mixed with sugar and presented to mice once
a day. Doses of these supplements were 50-100 mg/mouse per day Glyceryl
Oleate, 4-5 mg/mouse per day cholesterol, and TOO-150 mg/mouse per day
corn oil; the purity of these supplements was not stated. Four-week-old mice
were fed these diets and then bred within the same group. Their offspring were
maintained on the same diets as their parents from birth “until they died or be-
came moribund and were killed.” Survival rates for the individual groups were
not provided. The incidence of brain tumors in treated mice is shown in Table 5.
The report contained general histopathological descriptions of the tumors; how-
ever, no specific tumor type induced by Glyceryl Oleate was described. The
diets supplemented with lecithin, cholesterol, and cholesterol, in combination
with any other lipid, induced brain tumors in the largest number of mice.
In a similar experiment, the carcinogenicity of Glyceryl Oleate was eval-
uated in T.M. strain mice that were fed Purina Chow supplemented with refined
corn oil (Group 2), crude corn oil (Group 3), refined corn oil plus up to 1.5%
free fatty acids, oleic and linoleic acids (Group 4), and Glyceryl Oleate (Group 5)
at concentrations of 200 mglmouse per day. (93) Controls (Group 1) were fed
ASSESSMENT: GLYCERYLOLEATE 403

TABLE 5. Incidence of Brain Tumors in Mice Fed Various Egg Lipids’9*r

Total no. of No. of No. of mice

Diet supplement mice treated mice examineda with brain tumors

Control, no supplement 360 188 0

Corn oil 159 11 1

Cholesterol 212 80 20

Glyceryl Oleate 144 63 3

Corn oil and cholesterol 106 22 7

Glyceryl Oleate and cholesterol 158 64 7

aIt was not stated whether or not the mice that were not examined within each group died, and, if they died,
whether or not their deaths were associated with their respective dietary supplements.

Purina Chow alone. Offspring of the intragroup bred mice were maintained on
the same diets for a total of four-seven generations of mice. Mice were killed
when they were observed to lose weight rapidly. Three of the 195 control mice
in Group 1 developed gastric papillomas and squamous cell carcinomas, and
none developed pyloric or intestinal tumors. Gastric papillomas were also found
in 6/209 mice of Group 2, 49/196 mice of Group 3, 87/328 mice of Group 4, and
311166 mice of Group 5 (Glyceryl Oleate-supplemented diet). Fewer squamous
cell carcinomas were observed in all treatment groups: Group 2, l/209; Group
3, 61196; Group 4, 101328; Group 5, 6/166. Pyloric tumors were also recorded
for all treatment groups at the following frequencies: Group 2, 21209; Group 3,
g/196; Group 4, 41/328; Group 5, 311166. Free fatty acids in the preparations fed
to the mice that developed gastric tumors were considered the cause of the tu-
mors; however, the relative purity of the Glyceryl Oleate was not detailed. De-
tailed gross and microscopic descriptions of the tumors were recorded.

Antitumorigenicity

The in vivo antitumor activity of Glyceryl Oleate was studied using im-
planted Ehrlich ascites tumors in mice. (94) Saline solutions at two doses (6.0 and
1.5 mg/mouse per day) of Glyceryl Oleate were administered once daily for 5
successive days to two mice per dose. Tumor growth and body weight gain after
7 days and life spans were recorded. Whereas control mice died within 17 days,
both doses of Glyceryl Oleate prolonged the survival period of the mice (>30
days at 6.0 mg and an average of 24 days at 1.5 mg). Although both doses re-
sulted in an increase in body weight over 7 days, inhibition of tumor growth was
observed in mice only at the higher dose. Moderate tumor growth occurred at
the lower dose.

CLINICAL ASSESSMENT OF SAFETY

Dermal Irritation

Glyceryl Oleate, used in hand cream at 1.5%, was evaluated for primary der-
mal irritation in 15 and 30% aqueous preparations.(g5) Twenty subjects partici-
pated in the single insult occlusive patch test using the Draize-Shelanski tech-
404 COSMETIC INGREDIENT REVIEW

nique. The 15% concentration yielded 18 negative responses; the remaining 2

subjects had scores of 0.5 and 1 (max = 3). Seventeen individuals had negative
responses, and 3 had scores of 1 after treatment with the 30% solution (Table 6).
A single insult occlusive patch test was performed using 20 panelists by ap-
plying a fragrance preparation that contained 19.0% Glyceryl Oleate.(96) Nega-
tive results were found in 17 of 20 subjects (doubtful reactions were observed in
3 of 20 subjects), and the formulation’s skin irritation potential was “practically
nonexistent” (Table 6).

Cumulative Dermal Irritation

The Lanman-Maibach test(97*g8)was used to assess the cumulative irritation

potential of two sunscreen formulations containing 5% Glyceryl Oleate.(“) A
dose of 50 yllcm’was administered to the backs of 10 subjects under 23-h closed
patches for a total of 21 consecutive applications. Sites were cleaned before
scoring and at reapplication at the 24th hour. The total converted numerical
scores for all applications and subjects of the two formulations were 23 and 38
(maximum score = 630), ranking them as mild materials causing no experimen-
tal irritation. Positive responses to both formulations were not observed until at
least the 12th application in most subjects. Most of the points for the cumulative,
total scores were contributed by 1 subject alone (22/23 points, 26/38 points),
whereas the remaining 9 subjects had individual scores of O-3 (Table 6).

Sensitization

A repeated insult patch test (RIPT) using 200 people was used to evaluate a
15% aqueous solution of Glyceryl Oleate as a primary irritant, fatiguing agent,
and/or sensitizer.(‘OO) Sixteen 24-h occlusive patches were applied to the upper
arm on Mondays, Wednesdays, and Fridays. Nontreatment periods were stated
to be the days between alternate day applications and on weekends. No signs of
skin irritation were observed after exposure to Glyceryl Oleate in any of the ap-
plications (Table 6).
An RIPT with a sunscreen formulation containing 5% Glyceryl Oleate was
conducted using an occlusive patch technique. (lol) Ten 24-h induction patches
on Tuesdays, Thursdays, and Saturdays (sites were evaluated after removal of
each patch) were followed by a 12-l 6-day nontreatment period and a 24-h chal-
lenge patch at an adjacent site. These challenge sites were then evaluated imme-
diately after patch removal and 24 h later. None of the 15 subjects participating
in this study alone had positive reactions during the induction phase or when
challenged. Of the 37 others who were being tested simultaneously for photoal-
lergic and phototoxic responses to treatment, 2 subjects had transient reactions
of slight erythema (scores of 1 on scale of O-4) to induction patches, and all sub-
jects had no reaction to the challenge patch (Table 6).

Photoallergy and Phototoxicity

The potential of a sunscreen formulation containing 5% Glyceryl Oleate for

inducing photoallergy and phototoxicity in humans was evaluated by modifica-
tions of an RIPT.(‘O’) Approximately 200 mg of the formulation was applied
under an occlusive patch to the inner forearms of 29 subjects for the photoal-
ASSESSMENT: GLYCERYL OLEATE 405

lergy test and of 10 subjects for the phototoxicity test. After a 24-h exposure pe-
riod, the contact sites were evaluated after patch removal and irradiated with
UVA light (15 minutes at 4400 pW/cm2). The sites of subjects in the phototoxicity
test were then evaluated immediately following irradiation and 24 h and 48.h
later. The 24-h patch application and irradiation were repeated 10 times for sub-
jects in the photoallergy test on Mondays, Wednesdays, and Thursdays. After a
12-16 day nontreatment period, 24-h challenge patches were applied to adja-
cent sites. Photoallergy test sites were evaluated before and after irradiation
upon patch removal in both induction and challenge phases. Scoring was per-
formed at 48 and 72 h after application of challenge patches. No skin reactions
were observed in the 10 subjects participating in the phototoxicity test, and only
1 photoallergy test subject (n = 29) had a grade 1 reaction (scale O-4) to the sixth
induction patch at the nonirradiated control site. No positive reactions to induc-
tion or challenge patches were observed at any irradiated site (Table 6).

Oral Exposure to Glycerol

Data from subchronic human studies on the oral administration of glycerol,

a metabolic product of Glyceryl Oleate, were used in the safety assessment pro-
cess of glycerol for the federal regulation of GRAS substances.‘30.69’

SUMMARY

Glyceryl Oleate, the glyceryl 1-monoester of oleic acid, is dispersible in

water and soluble in acetone, simple alcohols, and cottonseed oil. Glyceryl Ole-
ate is manufactured by the partial hydrolysis of corresponding tri- and diglycer-
ides, by esterification of glycerol with oleic acid, or by glycerolysis of common
fats and oils.
Glyceryl Oleate is used primarily in cosmetic products as an emulsifier and
was listed as an ingredient in 716 of the cosmetic formulations reported to the
FDA in 1981. The FDA table had Glyceryl Oleate concentrations ranging from
10.1 to 5% in formulations that were predominantly lipsticks, eye shadows,
makeup bases, and skin care preparations.
Monoglycerides of edible fats or oils are considered GRAS and indirect food
additives for human consumption by the FDA. Glyceryl Oleate can be used as a
prior-sanctioned food ingredient and as a direct and indirect food additive. The
pharmaceutical industry uses Glyceryl Oleate as an inert carrier compound and
to enhance intestinal drug absorption.
Oral administration of a single 13 ml/kg dose of a sunscreen formulation
containing 5% Glyceryl Oleate to rats produced no signs of toxicity and no
lethality.
Undiluted and 50% in corn oil concentrations of Glyceryl Oleate used in
dermal irritation studies with rabbits were found to be minimally irritating. A vol-
ume of 0.5 ml of a sunscreen formulation containing 5% Glyceryl Oleate pro-
duced erythema and slight edema in rabbits.
Minimal to moderate eye irritation was produced by undiluted Glyceryl Ole-
ate, 50% Glyceryl Oleate in corn oil, and a fragrance preparation containing
 TABLE 6. Clinical Assessment of Safety of Clyceryl Oieate

Clyceryl
Oleate No. of
Material tested concentration Type of test humans Results/Comments Reference

Glyceryl Oleate 15% aqueous Test for skin irritation by 20 18/20 had score of 0 95
Draize-Shelanski SlOPTa l/20 had score of l/2
l/20 had score of 1
(max = 3)

Glyceryl Oleate 30% aqueous Test for skin irritation by 20 17/20 had score of 0 95
Draize-Shelanski SIOPT 3/20 had score of 1 8
(max = 3) 2

‘Qyceryl Oleate 15% aqueous RlPTb (16 patches, Mon., 200 No signs of skin irritation observed 100 7
z
Wed., Fri.) during induction or challenge (week-
ends considered nontreatment period)
z
-----------------------------------------------------------~--------------------------~------------------------------------------------------------------------------------------------------------------------------------------------
z
Fragrance preparation 19.0% Test for skin irritation by 20 17/20 had score of 0 96 0
G
SIOPT 3/20 had score of f
(max - 4) 5

Sunscreen formulation R
5% 21-day Cumulative lrritancy 10 Total converted numerical score of 23 99
<
Test (max = 630); mild material causing ;;1
no irritation g
Sunscreen formulation 5% Zl-day Cumulative lrritancy 10 Total converted numerical score of 38 99
Test (max = 630); mild material causing
no irritation

Sunscreen formulation 5% RIPT 52 15/52 were involved in RIPT alone; 101

none of the 15 had positive reactions;
37/52 were involved in simultaneous
photoallergy and phototoxicity test-
ing; 2/37 had transient, slight ery-
thema to induction patches; no reac-
tions to challenge patches observed

Sunscreen formulation 5% Photoallergy test by RIPT + 29 One subject had a score of 1 to the 101
UVA irradiation sixth induction patch at a nonirradi-
ated control site (max - 4); no posi-
tive reactions to induction or chal-
lenge patches at any irradiated site

Sunscreen formulation 5% Phototoxicity test single 10 No skin reactions observed 101

patch test + UVA irradia-

aSIOPT, single insult occlusive patch test.

bRIPT, repeated insult patch test.
408 COSMETIC INGREDIENT REVIEW

19.0% Glyceryl Oleate when administered to rabbits. A formulation containing

5% Glyceryl Oleate administered at a 0.1 ml dose to rabbit eyes induced slight
conjunctivitis.
Daily applications of 2.0 ml/kg of a 25.0% corn oil solution of a formulation
containing Glyceryl Oleate for 20 days produced severe dermal irritation in rab-
bits. In another 4-week dermal toxicity/phototoxicity study, product formula-
tions containing varying concentrations of two sunscreen ingredients produced
slight, reversible dermal irritation. Each sunscreen ingredient contained 5%
Glyceryl Oleate.
Glyceryl Oleate administration was associated with development of a few
brain tumors (3 tumors in 63 mice) in a two-generation study in mice of the T.M.
strain whose feed was supplemented with 50-100 mg/mouse per day Glyceryl
Oleate. Digestive tract tumors were found in T.M. strain mice fed 200 mg/mouse
per day Glyceryl Oleate (feed supplement) for four-seven generations and were
considered due to free fatty acid impurities. The Expert Panel found the results of
these studies equivocal.
Doses of 1.5 and 6.0 mglmouse per day of Glyceryl Oleate in saline in-
creased the survival period of mice with implanted Ehrlich ascites tumors; the
higher dose inhibited tumor growth.
Two aqueous Glyceryl Oleate preparations (15% and 30% concentrations)
and a fragrance preparation containing 19.0% Glyceryl Oleate were negative for
cutaneous irritation when tested on human skin using single insult occlusive
patch tests.
Two sunscreen formulations containing 5% Glyceryl Oleate were consid-
ered mild compounds and caused no irritation in a cumulative occlusive patch
test using human subjects.
No signs of irritation or sensitization were observed in humans after re-
peated insult patch testing of a 15% aqueous Glyceryl Oleate preparation and a
sunscreen formulation containing 5% Glyceryl Oleate. A few subjects involved
in simultaneous photoallergy and phototoxicity tests had slight, transient ery-
thematous responses. No positive reactions were observed at any irradiated site
during induction and challenge phases of the photoallergy test.
The metabolic products of Glyceryl Oleate are glycerol and oleic acid. The
use of these compounds in and for foods is regulated by the FDA. Subchronic
and chronic toxicity data from studies with animals and humans that were used
in the safety assessment of glycerides, glycerol, oleic acid and sodium oleate are
presented in this report.

CONCLUSION

Based on the data from animal and human studies included in this report,
the CIR Expert Panel concludes that Glyceryl Oleate is safe as a cosmetic ingredi-
ent in the present practices of use and concentration.
ASSESSMENT: GLYCERYL OLEATE 409

ACKNOWLEDGMENT

Mauri Y. Okamoto, Scientific Analyst and writer, prepared the technical

analysis used by the Expert Panel in developing this report. Word processing for
this report was performed by Karen Swanson.

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*Available upon request: Director, Cosmetic Ingredient Review, 1110 Vermont Ave., NW, Washington,
DC 20005.
412 COSMETIC INGREDIENT REVIEW

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ASSESSMENT: CLYCERYL OLEATE 413

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