JOURNAL OF THE AMERICAN COLLEGE OF TOXICOLOGY

Volume 5, Number 3, 1986

Mary Ann Liebert, Inc., Publishers

Final Report on
the Safety Assessment of
Hydroxyethylcellulose,
Hydroxypropylcellulose,
Methylcellulose, Hydroxypropyl
Methylcellulose, and Cellulose Gum

Hydroxyethylcellulose, Hydroxypropylcellulose, Methylcellulose, Hydroxy-

propyl Methylcellulose, and Cellulose Gum are modified cellulose polymers
that are used in cosmetic products at concentrations up to 10%. The cellulose
derivatives pass essentially unchanged through the gastrointestinal tract fol-
lowing oral administration. They are practically nontoxic when administered
by inhalation or by oral, intraperitoneal, subcutaneous, or dermal routes.
Subchronic and chronic oral studies indicate that the cellulose derivatives are
nontoxic when administered to laboratory animals. No significant teratogenic
or reproductive effects have been demonstrated. Ocular and dermal irritation
studies show that the cellulose derivatives are, at most, minimally irritating to
rabbit eyes and nonirritating to slightly irritating to rabbit skin when tested at
concentrations up to 100%. No mutagenic activity of these ingredients was
demonstrated. The cellulose derivatives at concentrations up to 100% were
nonirritating to mildly irritating, nonsensitizing, and nonphotosensitizing
when evaluated in clinical studies. It is concluded that the ingredients re-
viewed are safe as cosmetic ingredients in the present practices of use and con-
centration.

INTRODUCTION

he literature on Methylcellulose, Hydroxypropyl Methylcellulose, and Cellu-

T lose Gum dating from 1920 to 1973 has been previously reviewed in a GRAS
report and evaluation, and is only briefly summarized here.“,*’ A survey of the
most recent literature, pertinent articles not included in the GRAS report and

1
2 COSMETIC INGREDIENT REVIEW

evaluation, as well as the unpublished cosmetic industry data on these three cel-
luloses have been included. Hydroxyethylcellulose and Hydroxypropylcellulose
are reviewed in full.

CHEMICAL AND PHYSICAL PROPERTIES

General

Hydroxyethylcellulose (HEC), Hydroxypropylcellulose (HPC), Methylcellu-

lose (MC), Hydroxypropyl Methylcellulose (HPMC), and Cellulose Gum (CG) are
modified cellulose polymers with the general subunit structure:

‘llzG/, 0” .~q--J--&~~~

For HEC:“’ R = (-CHz-CHz-0-)nH n may equal zero

a + b + c = 1.5to3

For HPC:14) R = (-&Ha-O-),,H n may equal zero

a + b + c = usually 3

For MC:(‘) R = (-CH,) or H

a + b + c = 1.62 to 1.92

For H PMC: (‘I R = (-CH3) or (-C3Ha-O-),,H R may equal zero

a + b + c = 1.12 to 2.03

For CG:(‘) R = (-CH2-COONa) or H

a + b + c = 0.3 to 1.2

These cellulose ethers are derived from the reaction of the three free hy-
droxyl groups in the 2-, 3-, and 6- positions of the anhydroglucose unit of the
cellulose molecule. The number of hydroxyl groups reacting and the nature of
the substituent group largely determine the physical properties, particularly solu-
bility, of the product. The viscosity of the final product is greatly affected by the
molecular weight of the starting cellulose. All of these ethers are odorless, taste-
less, and very stable chemically.‘s)
ASSESSMENT: CELLULOSE POLYMERS 3

Hydroxyethylcellulose

HEC is a white, odorless, tasteless powder that has a pH of 6.5-8.5 as a 1%

aqueous solution. c9) It is soluble in hot and cold water, 70% soluble in alcohol,
and generally insoluble in organic solvents, with the exception of dimethylsulf-
oxide.(3.10) The surface chemical properties of HEC have been studied in depth
by H~lly(“*~*); HEC was found to be weakly surface active. The reader is referred
to Savage et al. (13) for a complete review of the chemistry of this ingredient. The
physicochemical properties of HEC and the other cellulose derivatives are listed
in Table 1.
HEC is prepared by reacting alkali cellulose with ethylene oxide in the pres-
ence of alcohol or acetone. The molar substitution, or MS, is the average num-
ber of moles of ethylene oxide that become attached to the anhydroglucose cel-
lulose unit at either the hydroxyl groups in the chain or at previously reacted
hydroxyl groups. The degree of substitution, or DS, is the average number of hy-
droxyl groups substituted per anhydroglucose unit.“‘) HEC is commonly manu-
factured with an MS of 1.8 and 2.5; 2.5 gives optimum water solubility and
strong resistance to enzymic attack. (l”*14) However, the various grades range
from an MS of 1.5 to 3.0. Solution viscosities vary greatly within each MS
level.(‘O) The DS ranges from 1.5 to 3 (max = 3).(3) HEC is one of the more valu-
able cellulose derivatives because it is available in a treated form that produces
rapid dispersion in aqueous solutions. (lo) Other specific grades may contain ad-
ditives to delay hydration, prevent lumping, and retard bacterial growth.(3)
HEC can be identified by close matching to a standard infrared spectrum
with no indication of foreign materials.(‘5)
Being nonionic in character, HEC does not react with polyvalent cations,
and in solution is generally unaffected by moderate shifts in pH. HEC is compati-
ble with sodium chloride (0.5-26%), alum (2.0%), ammonium sulfate (lO.O%),
atropine sulfate, pilocarpine-hydrochloric acid, detreomycin, zinc sulfate, potas-
sium iodide, and some anionic and amphoteric surfactants (12.5%) depending
on specific concentrations. (l”*16) Increased flocculating action on kaolin suspen-
sions has been demonstrated by HEC graft copolymerized with acrylamide.(“)
HEC has increased the dissolution rate of p-aminosalicylic acid tablets(‘8) and
also accelerated the release rate of chlorpromazine, dioxopromethazine, oxytet-
racycline, and sulfathiazole from hydrogels.‘19)
HEC is stable under the typical conditions of cosmetic use.t3)
Haugen et al.(14) studied the steady shear flow properties, rheological repro-
ducibility, and stability of aqueous HEC dispersions over a period of 5 years. Dis-
persions of 1.5-3.5% HEC had shear-thinning flow properties. Each 0.5% incre-
ment in polymer concentration substantially increased apparent viscosity and
non-Newtonian behavior. Over the 5-year storage period, apparent viscosity de-
creased with time, and behavior became more Newtonian within each disper-
sion concentration.
Solutions of HEC are susceptible to bacterial degradation and must be prop-
erly preserved for long-term stabiIity.(20) Eros and Csordas(21) studied the effect
of various preservatives and temperatures on the viscosity and stability of HEC
solutions over a 3-month period. The solution preserved with methyl 4-hydroxy-
benzoate remained nearly unchanged, whereas those without preservatives had
 P

TABLE 1. Physicochemical Properties

Values for

Property HEC HPC MC HPMC CG

Physical appearance White, odorless, White, odorless, White to off-white, White to off-white White to cream colored,
tasteless pow- tasteless gran- odorless, taste- fibrous pow- odorless, tasteless,
derW.W ular pow- less, fibrous der’1.6’ powder”,”
der’4.15’ powderC’.s)

Formula weight per anhydro- 206 minimum@’ 223 minimumr4’ 166.3-l 90.5r5’ 177-279’6’ 185-258”’
glucose unit
pH of:
1% aqueous solution 6.5-8.Sc9’ 6.0-8.0”“’ - 6.5-8.5(2’.29)
2% aqueous solution 6.0-8.0”s’ 5.0-8.Sc4’ - - 7.5”’
5% aqueous solution 6.O-8.5’3’ - - - -

Viscosity (Brookfield at
25T, cps)
1 % solids 800-5000”’ 40-2500’4,‘o’ 8’20’ - 69-O); 1000-5000”’
2% solids 25-6500f3’ 75-6500’*’ 1O-8000’=” 1O-8000’” 10-50 OOO”.‘.‘W
5% solids 75-400C3’ 25-400’*’ 400’20 - 11 5,500’zo’
10% solids - 1 oo-70014’ - - -

Particle size 90% minimum 95 and 99% - - -

through 40 minimums 30
mesh”’ and 20 mesh,
respectivelyC4’

Bulk density (g/ml) - 0.5”’ 0.25-0.70’“’ 0.25-0.70’6’ 0.75”’

Moisture (% maximum) 5,0’3.9.‘5’ 5 0’4.‘” 3.0, 507.19) 3 0 5 0”5,29’ 8.0, 1 0”7=‘1
., f
Ash (% maximum) 5.0’9’ 0.5C4’ 2.0, l.S”‘J9’ , ,5-3.0”5,m -

Sodium chloride (% maxi- - - 1 .O’J’ 0.5’6’ -

mum)
Sodium 9.5 after drying”‘]
 Heavy metals (maximum) - 40 ppm”” 10 ppmr291 10 ppm(29’ 40 PPm’27~29J
Lead - 10 ppmr”’ 10 ppmr*” 10 ppmr*‘j 10 ppm(“’
Arsenic - 3 ppmr2” 3 ppm’27.“’ 3 ppm”” 3 ppmr’”
Refractive index (2% aque- - 1.337’4’ 1.336”’ 1 .336’6’ -
ous, 2OOC)

Specific gravity
1% aqueous - - 1.0112’“’ 1.0112’6’ -
5% aqueous - - 1 .0117’5’ 1.0117’6’ -
10% aqueous - - 1 .O245’5’ 1 .0245r6’ -
Solubilitya
Water S’3.W Sat <4O”C; S (cold only)“.20’ C,(cold only)“W”’ D,“” ~“0,
I at >40°C(20)
Alcohol s (to 70%)“0’ S”“’ ,,I) - ,,I1
Organic solvents S-Dimethylsulf- S in polar sol- S-glacial acetic S-most polar ICI)
oxide only(“‘) vents(20’ acid, and limited s01vents’25’
numberr’.27)
Surface activity (in water)
Surface tension (dynes/cm) 64”O’ 45’10’ 5O”O’ 71 (10)
Interfacial tension Reduced(‘O) Greatly re- Reduced”O) Unchanged”o’
ducedr”’
Film properties
Tensile strength (psi) 4OOO”O’ 2OOO”O’ - 3ooo”0’ 12,000”~’
Elongation at break 25%“0’ 50% “0’ - 35%“Q’ 10% ‘I”’
Flexibility (at 50% relative Cood”O’ Excellent - Good”“’ PoorilOi
humidity [R.H.])
Equilibrium moisture con- ‘jO,o”O’ 3%“0’ - 4% ,101 15%“O’
tent (at 50% R.H.)
Blocking tendency (at 90% Some None(l”) - Littlell”’ Considerable”“’
R.H.)
Density of film - - - - 1.59 g/ml”)
Minimum ignition tempera- 420°C’28’ - - - -
ture

as, soluble; I, insoluble; D, disperses.

6 COSMETIC INGREDIENT REVIEW

significant decreases in viscosity related to time. The viscosity of all solutions de-
creased exponentially with temperature increase.
HEC has demonstrated synergistic viscosity when combined with an equal
amount of an anionic cellulose derivative. The resultant viscosity has been al-
most double that expected. HEC (viscosity of 1800 cps) combined with CG (vis-
cosity of 1500 cps) had an actual viscosity of 3200 cps when the expected vis-
cosity was 1650 cps. (lo)

Hydroxypropylcellulose

HPC is a white, hygroscopic, odorless, and tasteless granular powder. This

nonionic polymer is soluble in water, below 4O”C, alcohol, and most polar or-
ganic solvents. GO)A 2% aqueous solution has a pH of 5.0 to 8.5r4) (Table 1). The
reader is referred to Desmarais (**I for a complete review of the chemistry of this
ingredient.
HPC is prepared commercially by reacting cellulose with sodium hydroxide
and propylene oxide under proprietary conditions. The DS is usually 3;(4) the
MS is usually greater than 3. (*O)Silicon dioxide (0.3%) may be added as an anti-
caking agent.(4)
HPC can be identified by close matching to a standard infrared spectrum
with no indication of foreign materials.(15)
HPC is stable under typical cosmetic use conditions.(4) Solutions are gener-
ally stable in the pH range of 3-10. HPC is available in several viscosity types
and is compatible with most common inorganic salts (at low salt concentration)
and with most natural gums and synthetic water-soluble polymers. Viscosity in-
creases rapidly with concentration. Aqueous solutions of HPC exhibit Newton-
ian behavior at low shear rates but become more thixotropic at high shear rates.
HPC is very surface-active, has good film-forming properties, and forms films
with excellent flexibility and heat-sealing properties. (*O)It is particularly useful as
an emulsifier and thickener in oil-in-water emulsions.(10*20)

Methylcellulose

MC is a white to off-white, odorless, tasteless, hygroscopic powder.(s) It is

soluble in cold water, glacial acetic acid, and in a mixture of equal parts ethanol
and chloroform, whereas it is insoluble in hot water, ethanol, ether, and chloro-
form.(20.23) (Table 1). The reader is referred to Savage et al.(13) and Greminger
and Savage(24) for a complete review of the chemistry of this ingredient.
MC is prepared by reacting cellulose fibers (cotton linters or wood pulp)
with caustic soda to produce alkali cellulose, which is then reacted with methyl
chloride. The product is purified and ground. The extent of alklylation and poly-
mer chain length are controlled in order to produce a derivative with specific
characteristics. For cosmetic use, the DS ranges from 1.62 to 1 .92.(5) This is
within the DS range that has maximum water solubility.(20)
MC can be identified by close matching to a standard infrared spectrum with
no indication of foreign materials.(23)
MC is stable under typical cosmetic use conditions.‘5) Solutions of MC in-
crease in viscosity on heating and eventually gel at 50-55OC. This gel point can
be elevated by the addition of ethanol or propylene glycol, while most electro-
ASSESSMENT: CELLULOSE POLYMERS 7

lytes, as well as sucrose, glycerol, and sorbitol, depress the gel point. MC solu-
tions, being neutral and nonionic, are relatively stable over a pH range of 3-l 1
and are not affected by ordinary concentrations of electrolytes or other sol-
utes.(*O) The presence of inorganic salts does increase solution viscosity. Clear
water-soluble films may be cast from aqueous or mixed solvent (methanol-
water) solutions of MC.(20s25)

Hydroxypropyl Methylcellulose

HPMC is a white to off-white, fibrous, hygroscopic powder.(6.1s) It is soluble

in cold water and in most polar organic solvents (*OSLO) (Table 1). The reader is re-
ferred to Greminger and Savage (24)for a complete review of the chemistry of this
ingredient.
HPMC is prepared by reacting cellulose fibers (cotton linters or wood pulp)
with caustic soda, methyl chloride, and propylene oxide. This product is purified
and ground. The extent of alkylation and polymer chain length are controlled in
order to produce a derivative with specific characteristics. For cosmetic use, the
DS ranges from 1 .12 to 2.03, (6) with the number of methoxyl substitutions typi-
cally much larger than the number of hydroxypropyl substitutions.‘lO)
HPMC can be identified by close matching to a standard infrared spectrum
with no indication of foreign materials.(23)
HPMC is stable under typical cosmetic use conditions.(6) Aqueous solutions
are surface-active, form films upon drying, and exhibit thermogelling properties.
Depending on the amounts and ratios of methyl and hydroxylpropyl groups, the
gel point can be raised as high as 85-90°C in commercial products.(10~20,25)

Cellulose Gum
CC is a white to cream-colored, hygroscopic, odorless, and tasteless pow-
der. Chemically, it is the sodium salt of carboxymethylcellulose (CMC). It is in-
soluble in alcohol, ether, and in most organic solvents, but disperses easily in
water to form a viscous solution (23) (Table 1). The reader is referred to Savage et
al.‘13) and Batdorfc26) for a complete review of the chemistry of CG.
Because CMC is spontaneously converted to the sodium salt in alkaline solu-
tion, much of the literature makes no distinction between the two.‘*) Therefore,
pertinent information on CMC has been included in this report.
CG is manufactured by treating cellulose (cotton Iinters or wood pulp) with
alkali followed by reaction with sodium monochloroacetate. The resulting prod-
uct is then purified. (‘I The reaction is controlled to give the desired DS degree of
polymerization (DP) and uniformity of substitution, as this determines the prop-
erties of the finished product. (*O) For cosmetic use, the DS ranges from 0.3 to
1.2.C’)
CG can be identified by close matching to the CTFA standard infrared spec-
trum with no indication of foreign materials.(23)
CG is stable under typical cosmetic use conditions.“) It exhibits a reversible
loss of viscosity on heating. Solutions are fairly stable between pH 5 and 11. CG
is compatible with most other water-soluble gums and is generally unaffected by
high concentrations of monovalent salts. (10*20)It forms clear films that are resis-
tant to oils and most organic soIvents.(20)
8 COSMETIC INGREDIENT REVIEW

USE

Cosmetic Uses

The cellulose derivatives are used in a wide variety of cosmetics and toilet-
ries as thickeners, suspending agents, film formers, stabilizers, emulsifiers, emol-
lients, binders, or water-retention agents. (3-7.10)Generally, the majority of uses is
in hair products, eye and facial makeups, and skin care preparations. The con-
centration of use can range up to 10%. However, the celluloses are most fre-
quently used in concentrations of >O.l-1% (30) (Table 2).
The FDA cosmetic product formulation data presented in Table 2 are com-
piled through voluntary filing of such data in accordance with Title 21 part 720.4
(d) (1) of the Code of Federal Regulations (1979). Ingredients are listed in pre-
scribed concentration ranges under specific product type categories. Since cer-
tain cosmetic ingredients are supplied by the manufacturer at less than 100%
concentration, the value reported by the cosmetic formulator may not necessar-
ily reflect the actual concentration found in the finished product; the actual con-
centration in such a case would be a fraction of that reported to the FDA. Since
data are only submitted within the framework of preset concentration ranges,
there is also the opportunity for overestimation of the actual concentration of an
ingredient in a particular product. 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 2- to lo-fold error in the assumed ingredient
concentration.(30)
The formulation data presented in Table 2 indicate that cosmetic products
containing the cellulose derivatives may contact all external body surfaces and
hair, as well as ocular and vaginal mucosae. HEC, MC, and CG also have the po-
tential to contact the oral mucosae. These products may be used daily or occa-
sionally over a period of up to several years. The frequency and length of appli-
cation could result in continuous exposure.
HEC, HPC, and CG are approved for use in cosmetics in ]apan.(31)

Hydroxyethylcellulose
In 1981, HEC was used in a total of 422 formulations, most of which were
hair, hair coloring, eye makeup, and skin care preparations. Of these 422, 71%
incorporated HEC at concentrations of >O.l-1 %; 22% at concentrations of > l-
5%; 6% at concentrations 10.1%; and ‘less than 1% at concentrations >5-
1o”/o.‘30’

Hydroxypropylcellulose
In 1981, HPC was used in a total of 82 formulations, most of which were fra-
grance and hair (noncoloring) preparations. Of these 82, 90% incorporated HPC
at concentrations of >O.l-1; 9% at concentrations of >l-5%; and 1% at con-
centrations 10.1 o/o.(3o)

Methylcellulose
In 1981, MC was used in a total of 144 formulations, most of which were
blushers, eye makeup, and skin care preparations. Of these 144, 53% were of
unreported MC concentration; 17% at concentrations of >O.l-1 %; 16% at con-
centrations of >l-5%; and 13% at concentrations ~0.1°/o.(30)
 TABLE 2. Product Formulation Data’30’

No. of product formulations within

each concentration range (%)
Total no. of Total no.
formulations containing Unreported
Product category in category ingredient concentration >5-10 >l-5 >o. l-7 ao. 7

Hydroxyethylcellulose
Bubble baths 475 3 - - - 3 -
Eyeliner 396 19 9 10 -
Eye shadow 2582 12 - 12 -
Mascara 397 54 7 43 4
Other eye makeup preparations 230 7 1 6 -
Colognes and toilet waters 1120 1 - - - 1 -
Perfumes 657 11 - - - 11 -
Hair conditioners 478 55 16 38 1
Hair straighteners 64 6 2 4 -
Permanent waves 474 10 1 9 -
Hair rinses (noncoloring) 158 7 - - 3 3 1
Hair shampoos (noncoloring) 909 16 - - 2 14 -
Wave sets 180 3 - 3 -
Other hair preparations (noncoloring) 177 4 2 2 -
Hair dyes and colors (all types requiring caution statement 811 56 31 25 -
and patch test)
Hair rinses (coloring) 76 52 - - - 34 18
Hair bleaches 111 4 - 1 3 - -
Other hair coloring preparations 49 1 1 - -
Blushers (all types) 819 3 - 3 -
Face powders 555 1 - 1 -
Makeup foundations 740 10 - - - 10 -
Makeup bases 831 6 - 6 -
Other makeup preparations (not eye) 520 1 1 - -
Nail creams and lotions 25 - - 1
Dentifrices (aerosol, liquid, pastes, and powders) 42 - 1 -
Bath soaps and detergents 148 - - 1 1 -
Deodorants (underarm) 239 - 2 -
Other personal cleanliness products 227 - 4 -
Aftershave lotions 282 - 1 1
TABLE 2. (Continued) s

No. of product formulations within

each concentration range (%)
Total no. of Total no.
formulations containing Unreported
Product category in category ingredient concentration >5-10 >l-5 >O.l-1 50.1

Shaving cream (aerosol, brushless, and lather) 114 - - - 1

Skin cleansing preparations (cold creams, lotions, liquids, 680 7 - - 4 3 -
and pads)
Depilatories 32 6 - - 2 4 -
Face, body, and hand skin care preparations (excluding 832 12 - - 3 8 1
shaving preparations)
Moisturizing skin care preparations 747 18 - - - 18 -
Paste masks (mud packs) 171 10 - 2 3 5
Skin lighteners 44 2 - - - 2 -
Skin fresheners 260 2 - - - 2
Wrinkle smoothers (removers) 38 1 - - - 1 -
Other skin care preparations 349 6 - - 2 4 -
Suntan gels, creams, and liquids 164 3 - - - 3 -

1981 TOTALS 422 - 3 94 298 27

Hydroxyp,ropylcehlose
Bath oils, tablets, and salts 237 2 - - - 2 - 8
Bubble baths 475 1 - - - 1 -
Other bath preparations 132 3 - - 3 - 5
Eyeliner 396 - - - - E
Colognes and toilet waters 1120 3 - - - 3 - 2
Perfumes 657 38 - 36 1
- - 52
Other fragrance preparations 191 14 2 12
Hair conditioners 478 6 - 5 - i
Hair rinses (noncoloring) 158 1 - - 1 -
Hair shampoos (noncoloring) 909 2 2 - - 5
Tonics, dressings, and other hair grooming aids 290 1 - 1 - R
Wave sets 180 1 - 1 - <
1 - - F
Other hair preparations (noncoloring) 177 1
s
 Nail polish and enamel remover 41 - -
Deodorants (underarm) 239 -
Aftershave lotions 282 -
Other shaving preparation products 29 -
Face, body, and hand skin care preparations (excluding 832
shaving preparations)
Skin fresheners 260 - -
Suntan gels, creams, and liquids 164

1981 TOTALS 82 74 1

Methy/cellu/ose
Bubble baths 475 1 - - - 1 -
Eyeliner 396 13 - - 10 2 1
Eye shadow 2582 5 1 - 1 2
Eye makeup remover 81 2 - 2 - -
Mascara 397 1 1 - - - -
Other eye makeup preparations 230 1 - - 1 - -
Colognes and toilet waters 1120 4 4 - - - -
Other fragrance preparations 191 1 1 - -
Hair conditioners 478 1 -
Hair shampoos (noncoloring) 909 8 -
Wave sets 180 1 -
Hair dyes and colors (all types requiring caution statement 811
and patch test)
Hair rinses (coloring) 76 4 - -
Hair shampoos (coloring) 16 1 - - -
Blushers (all types) 819 59 55 - -
Makeup foundations 740 1 - - -
Lipstick 3319 1 - - -
Rouges 211 1 - - -
Other makeup preparations (not eye) 530 4 - -
Cuticle softeners 32 2 - 2
Deodorants (underarm) 239 1 - - -
Other personal cleanliness products 227
Aftershave lotions 282 4 - - 2
Skin cleansing preparations (cold creams, lotions, liquids, 680 6 1 3 1
and pads)
TABLE 2. (Continued)

No. of product formulations within

each concentration range (%J
Total no. of Total no.
formulations containing Unreported
Product category in category ingredient concentration >5-10 >J-5 >O.J-J SO. J

Face, body, and hand skin care preparations (excluding 832 3 - - - 1 2

shaving preparations)
Moisturizing skin care preparations 747 6 2 - - 4 -
Night skin care preparations 219 1 - - - - 1
Paste masks (mud packs) 171 1 1 - - - -
Wrinkle smoothers (removers) 38 1 - - - 1 -
Other skin care preparations 349 7 5 - 2 - -
Other suntan preparations 28 1 - - - 1 -

1981 TOTALS 144 76 - 23 25 20

Hydroxypropl Methylcellulose

Baby products 15 - -
Bath oils, tablets, and salts 237 - -
Bubble baths 475 8 - - - -
Other bath preparations 132 4 2 - 1 -
Eyeliner 396 3 1 - 1 -
Eye shadow 2582 3 - - - -
Mascara 397 6 - - 2 1
Other eye makeup preparations 230 2 - - 1 -
Hair conditioners 478 4 - - - 4 -
Hair rinses (noncoloring) 158 6 - - 2 4 -
Hair shampoos (noncoloring) 909 87 - 22 64 1
Hair dyes and colors (all types requiring caution statement 811 3 - 1 2 -
and patch test)
Hair shampoos (coloring) 16 2 - - - 2 -
Hair bleaches 111 11 2 7 2 -
Makeup preparations (not eye) 530 - - 1 -
Cuticle softeners 32 2 - 2 -
Bath soaps and detergents 148 5 - - 5 -
- - 3 6 -
Deodorants (underarm) 239 9
- - - 1 -
Douches 26 1
227 3 - - - 3 -
Other personal cleanliness products
282 1 - - - 1
Aftershave lotions
680 10 - 2 5 3
Skin cleansing preparations (cold creams, lotions, liquids,
and pads)
832 2 - - 1 1
Face, body, and hand skin care preparations (excluding
shaving preparations)
Moisturizing skin care preparations 747 4 - - - 4 -
- - - 2 -
Night skin care preparations 219 2
Paste masks (mud packs) 171 9 - 1 6 2 -
38 1 - - - - 1
Wrinkle smoothers (removers)
- - 3 1 -
Other skin care preparations 349 4
164 1 - - 1 -
Suntan gels, creams, and liquids
Other suntan preparations 28 1 - - 1 -

1981 TOTALS 197 3 3 53 130 8

Cellulose Cum
- - 5 -
Bath oils, tablets, and salts 237 5
Eyeliner 396 43 16 - 20 7

Eye shadow 2582 61 6 5 29 21

Mascara 397 19 - - 19 -
230 16 - 13 3
Other eye makeup preparations
2 - - 2 -
Sachets 119
Other fragrance preparations 191 4 - - 2 2
- - 1 -
Hair conditioners 478 1
Hair shampoos (noncoloring) 909 3 - - 3 -
2 - - 2 - -
Tonics, dressings, and other hair grooming aids 290
- - 1 -
Wave sets 180 1
1 - 1 - -
Hair dyes and colors (all types requiring caution statement 811
and patch test)
Hair bleaches 111 1 - 1 - -
819 50 2 1 39 8
Blushers (all types)
1 - -
Face powders 555 1
 f

TABLE 2. (Continued)

No. of product formulations within

each concentration range (%J
Total no. of Total no.
formulations containing Unreported
Product category in categorv ingredient concentration >5-JO >l-5 >O. J-J 50.1

Makeup foundations 740 239 35 - - 185 19

Lipstick 3319 2 1 - - - 1
Makeup bases 831 220 18 - 1 177 24
Rouges 211 6 - - - 6 -
Makeup fixatives 22 3 3 - - - -
Other makeup preparations (not eye) 530 14 5 - - 9 -
Cuticle softeners 32 1 - - 1 - -
Other manicuring preparations 50 1 - - - 1 -
Dentifrices (aerosol, liquid, pastes, and powders) 42 12 - - 8 4 -
Bath soaps and detergents 148 1 - - - - 1
Other personal cleaniness products 227 3 - - - 3 -
Aftershave lotions 282 2 - - - 1 1
Other shaving preparation products 29 1 - - - 1 -
Skin cleansing preparations (cold creams, lotions, liquids, 680 18 - - 2 11 5
and pads)
Face, body, and hand skin care preparations (excluding 832 26 - - 1 17 8 6
shaving preparations)
z
Moisturizing skin care preparations 747 31 4 - - 23 4 7
Night skin care preparations 219 1 - - - 1 - 5
Paste masks (mud packs) 171 9 -- -- -- 91
Skin fresheners 260 1 -- 2
Wrinkle smoothers (removers) 38 3 - - 1 2 - 52
Other skin care preparations 349 5 - - - 3 2 $
Suntan gels, creams, and liquids 164 3 - - - 3 -
z
-I
1981 TOTALS 812 90 - 25 591 106 E
<
7
s
ASSESSMENT: CELLULOSE POLYMERS 15

Hydroxypropyl Methylcellulose
In 1981, HPMC was used in a total of 197 formulations, most of which were
hair shampoos, eye makeup, and skin care preparations. Of these 197, 66% in-
corporated HPMC at concentrations of >O.l-1%; 27% at concentrations of
> l-5%; 4% at concentrations 10.1%; and 2% at concentrations of >5-
1o”/o.‘30’

Cellulose Gum
In 1981, CG was used in a total of 812 formulations, most of which were eye
and skin makeup and skin care preparations. Of these 812, 11% incorporated
CG at unreported concentrations; 73% at concentrations of >O.l-1 %; 13% at
concentrations 10.1%; and 3% at concentrations of > 1 -5°/o.(30)

Noncosmetic Use

Hydroxyethylcellulose
HEC has a myriad of uses in the industrial, medical, dental, veterinary, and
diagnostic fields. It is used as a thickener and emulsifier in disinfectant solutions,
antimicrobial pastes, pesticides, paints, and paint removers. HEC alone, and as a
graft copolymer, is utilized as a flocculating agent in the treatment of waste
waters. It is used for its film-forming effect in selective insecticides and in reme-
dies for the treatment of spilled hazardous liquids.(3z-40)
In the pharmaceutical industry, HEC is used extensively as a binder and ad-
juvant in tableting, as a thickener and stabilizer in artificial tears, medicated eye
drops, and contact lens solutions. Additionally, HEC is found in contraceptives
and other vaginal products and in compositions for the treatment of oral and na-
sal mucosal infections. It is also used as the vehicle or suspending agent for intra-
venous and intraperitoneal instillation of water-insoluble drugs and other com-
pounds. (41-58)
In the medical field, HEC is the protective polymer for activated carbon in
hemoperfusion and artificial kidney devices. It is the drag-reducing agent used to
decrease the hemolysis rate during the mechanical pumping of blood in open-
heart and other surgeries. HEC is used as a suspending agent for chemicals and
in the treatment of phosphorus burns. It is used as an absorbent in surgical dress-
ings, bandages, and sponge substitutes and is used in adhesives for surgical tapes
to improve moisture permeability.(59-71)
In dentistry HEC is used in pastes and sponge substitutes to provide enamel
protection and in film-forming compositions for the removal of nicotine tar from
teeth. The veterinary field uses HEC as a thickening and film-forming agent in a
composition for the prevention of bovine mastitis. HEC is also used as a viscosity
controller, film-coating polymer, and suspending agent in various diagnostic
techniques.(72-84)
HEC is listed as an indirect food additive for use as an adhesive component
(with no limitations), polymeric coating used in producing, treating, packaging,
transporting, or holding food, and in a water-insoluble form in cellophane sheets
and films for food packaging (with no limitations).(85-88)
16 COSMETIC INGREDIENT REVIEW

Hydroxypropylcellulose
HPC is used in the pharmaceutical industry as a tablet-coating agent, topical
protectant, and ophthalmic vehicle. It is found in menstrual tampons and in
medicated compositions applied to vaginal and nasal mucosae.~2s~47~50~89-95~
HPC is also used as a binder in ceramics and glazes, in vaccum-formed con-
tainers and blow-molded bottles, and as a suspending agent in PVC polymeriza-
tion. (*‘)
HPC is listed as a direct food additive (DFA) for use as an emulsifer, film
former, protective colloid, stabilizer, suspending agent, or thickener in accor-
dance with good manufacturing practices (GMPs). It is also approved as a binder
and disintegrator in tablets or wafers containing dietary supplements of vitamins
and/or minerals.(g6) As an indirect food additive (IFA), HPC is used as a basic
component of food contact surfaces.(87’

Methylcellulose and Hydroxypropyl Methylcellulose

MC and HPMC are used in the pharmaceutical industry as film formers and
tablet-coating agents, bulking and suspending agents, surfactants, thickeners,
stabilizers, and protective colloids. The FDA OTC (over-the-counter) drug review
program concluded that MC was safe in the amounts usually taken orally (2
g/day) in antacid products but that insufficient data existed to prove its effective-
ness.““‘) Subsequently, no data were submitted during the 2-year probationary
period, and MC is now classified as generally not safe or effective for antacid
use. (g8)
MC and HPMC are used in agricultural sprays, ceramics, cements, paints,
textiles, and papers. (24) MC is also used as a veterinary laxative in daily to twice
daily doses of 0.5-l .O g for cats and 0.5-5.0 g for dogs.(g9’
MC has been approved by FDA as a multiple-purpose GRAS (generally rec-
ognized as safe) food substance. (loo) HPMC is approved as a DFA when used in
accordance with GMPs.(‘O’) Both of these ingredients are used in foods as emul-
sifiers, film formers, protective colloids, stabilizers, suspending agents, or thick-
ener.(24.101) As IFAs, HPMC and MC are used as adhesive components and poly-
meric coatings in the production, treatment, packaging, transporting, and/or
holding of food; (85,86*102)
MC is also used in paper and paperboards as a defoam-
ing agent.(lo3) MC was first used in foods in the United States in 1960.“)

Cellulose Gum
CG is used in the pharmaceutical industry as a tablet excipient, suspending
and viscosity increasing agent, bulk laxative, demulcent, dental adhesive, and as
an absorption medium. (25,1o4*1o5) The FDA OTC drug review program concluded
that CG was safe in the amounts usually taken orally (3 g/day) in antacid prod-
ucts but that insufficient data existed to prove its effectiveness.(g7) Subsequently,
no data were submitted during the 2-year probationary period, and CG is now
classified as not safe or effective for antacid use.(98)
CG is used widely in textiles, paper, adhesives, insecticides, paints, ce-
ramics, lithography, and detergents. (20) It is used in veterinary drugs as a sus-
pending agent.
CG has been approved by FDA as a multiple purpose GRAS food addi-
tive.(106*107) It functions as a stabilizer, protective colloid, bulking agent, and
ASSESSMENT: CELLULOSE POLYMERS 17

water-retention agent. (*O)CG is also approved as a secondary DFA for specific

use in boiler water,(108) and as an IFA used in adhesives and polymeric coatings
for the packaging and transporting of food. (85,86)CG was first used in foods in the
United States in 1945.“)

GENERAL BIOLOGY
Biochemical Effects

Okada and Fletcher(lo9) studied the inactivation by radiation of deoxyribo-

nuclease I in aqueous solution with high concentrations of HEC. Inactivation of
the enzyme depended on the concentrations of both HEC and the enzyme;
however, it was not influenced by the viscosity of the system. Each increase of
HEC resulted in an increase in the dose of radiation required to inactivate the en-
zyme.
The oral administration of 500 and 1000 mg/kg HPC did not influence the
mobility of barium sulfate in the small intestine of mice, the formation of stress
ulcers in rats, or the bile secretion in rats.(“O)
The effects of MC on the absorption of nitrofurantoin administered orally to
humans was studied. MC (5.0% solution) delayed the absorption and urinary ex-
cretion without altering the bioavailability of nitrofurantoin.(‘,“‘) A similar delay
in the intestinal absorption of sulfafurazole suspended in MC was noted in
rats.(“*) MC and CC did not exhibit an inhibitory effect on the intestinal absorp-
tion of acetaminophen in rats.(l13)
Phenytoin and hexobarbital hydrophilized with MC demonstrated increased
gastrointestinal bioavailability both in vitro (tests with treated plugs vs pure drug)
and in vivo (study in human volunteers) .(l14.11’) Oral absorption of acetohex-
amide and tolbutamide in rats was improved by using capsule formulations con-
taining MC and HPMC.(‘16)
The ocular pharmacokinetics of pilocarpine-HCI in human eyes were stud-
ied using HPMC as a vehicle. The amount of pilocarpine-HCI absorbed in-
creased with increasing concentrations of HPMC.‘“‘)
Dietary fibers, including CG, were studied for their effects on the gastrointes-
tinal absorption of cadmium. CG produced a slight decrease in the cadmium
content of the tissues of rats following a single oral administration of the metal.
However, a significant decrease in the cadmium content of the tissues was noted
in rats fed continuously with a diet containing cadmium and CG. The inhibitory
effects of the fibers on the gastrointestinal absorption of cadmium appear to be
due to their intrinsic properties, particularly binding ability and viscosity.‘“8’
CG, as a dietary fiber at 5% in the diet, had no significant effect on the serum
lipids and liver lipid metabolism and urinary ascorbic acid content in rats fed
0.03% polychlorinated biphenyls (PCBS).‘“~)
Weanling rats fed a basal diet containing 4% amaranth (food Red No. 2) and
CG had less growth retardation than those receiving a basal diet with amaranth
alone. CG had a moderate protective effect against the toxicity of amaranth.(120)
Aspirin and salicylic acid suspended in 1% wt/vol dispersions of CG were
absorbed in significantly greater amounts from the gastrointestinal tract of rabbits
than when administered alone. The effect of viscosity on the gastric emptying
18 COSMETIC INGREDIENT REVIEW

rate apparently was responsible for the variation in bioavailability of aspirin from
the suspensions.(‘*‘)
A 1 O/O solution of CMC in saline administered intraperitoneally (ip) (0.2 ml/l0
g) to mice 5 hours before an ip injection of doxorubicin enhanced the hepato-
toxicity of this antibiotic. Lethality increased to 80% compared to 15% in mice
administered doxorubicin alone. The heart, liver, kidneys, and small bowel were
examined microscopically and the incidence and severity of hepatic damage
were increased in mice receiving both doxorubicin and CMC. A significant re-
duction in hepatic glutathione was noted in mice receiving CMC and doxorubi-
tin plus CMC in comparison to the controls and mice receiving doxorubicin
alone (l**) CMC also mildly decreased hepatic glutathione concentrations in
hamsters. (123)
A 1% (wt/vol) solution of CMC added to fetal calf serum (15%) stimulated a
dissociation of cellular aggregates and an extensive outgrowth of neurites in
mouse neuroblastoma cells. Neurite formation increased proportionally with the
concentration of CMC during the first 24 h of incubation, plateauing at 1 O/O CMC.
In rat pheochromocytoma cells, the addition of CMC in the absence of nerve
growth factor (NGF) produced no significant neurite outgrowth; however, cells
pretreated with CMC for 1 day responded to NGF with a more rapid rate of neu-
rite outgrowth than control cells not pretreated with CMC. The extent of out-
growth in this case was the same. Neither dialysis of CMC nor batch treatment of
culture medium with CMC prior to incubation enhanced neurite outgrowth. In-
cubation on CMC-coated dishes also did not enhance outgrowth. The effects of
CMC were attributed to possible increased cell-substratum adhesion or to
changes in cell membrane permeability.(124)

Tissue Effects

The efficacy and toxicity of intraocularly administered MC were studied in

rabbits. The three-part study consisted of an in-vitro cornea1 endothelial perfu-
sion test, an intraocular pressure test following anterior chamber injection, and
an endothelial abrasion test. A 0.4% MC solution in saline was nontoxic to the
cornea1 endothelium. Injection of the same into the anterior chamber moder-
ately increased intraocular pressure, although this was stabilized in the normal
range by 24 h. The MC solution provided only minimal endothelial protection
from polymethylmethacrylate intraocular lens surfaces.(125)

Physiological Effects

HEC of approximate molecular weight 30,000 was injected intravenously (iv)

in mice in doses of 600 to 1200 mg/kg in a study of vascular permeability effects.
The mice also received an iv injection of Evans blue immediately after the ad-
ministration of HEC; bluing of the ears was used as the indicator of increased
vascular permeability. HEC failed to cause bluing of the ears in any of the test an-
imals and therefore was not associated with an increase in vascular permeabil-
ity. (126)
Surgical procedures were carried out on 7 mongrel dogs involving the inser-
tion of a hot film anemometer probe into the left renal artery adjacent to the wall
ASSESSMENT: CELLULOSE POLYMERS 19

of the descending aorta. This allowed measurements of aortic wall flow dis-
turbance distal to a controlled partial occlusion. HEC was administered through
a femoral vein catheter as a 0.5% solution in 0.9% saline to test its effects as a
vascular drag-reducing agent. Administration continued up to a concentration of
60 ppm by weight in the bloodstream. HEC was relatively inefficient in reducing
vascular wall disturbances due to its lack of efficiency in imparting viscoelastic
character to the blood.(‘*‘) However, other experimenters have reported that
adequate levels of viscoelasticity may exist in HEC at concentrations of 500-700
ppm. (128)
Two groups of rabbits were used in electroretinograph studies conducted
under identical circumstances except for different coating agents on the cornea1
electrode surface consisting of ophthalmic artificial tear solutions containing 1.6
and 0.2% HEC, respectively. Five humans were also similarly studied. Retinal re-
sponses obtained with the 0.2% HEC tear solution increased up to 81% in
comparison to the values recorded with the 1.6% solution. The difference in
electrical conductivity of the two solutions was correlated with differences in
electroretinographic amplitudes and was also time dependent.(129)
Aqueous solutions of HPC at concentrations of 0.5 and 1 .O% did not cause
local anesthesia in the cornea of the 6 rabbits tested.
The physiological effects of repeated ip injections of MC have been studied
in mice(‘30-133) and in rats.(134-136) Stang and Boggs’130) injected mice with 0.5 ml
of a 2.5% MC solution three times weekly for 4 weeks. They found that MC pro-
duced a partially compensated hemolytic anemia, thrombocytopenia, neutro-
philia, increased splenic hematopoiesis, and hepatic hematopoiesis. These
changes were attributed to reticuloendothelial hyperplasia caused by macro-
phage ingestion of MC. Changes in the blood cells became fairly steady after 2
weeks of MC injection and were not affected by splenectomy. Pfrimmer et
al.(131) also studied the effects on mice after similar injections of MC and found
that MC was still visible in macrophages of the spleen and liver up to 40 weeks
later. Twice weekly injections of 2.5% MC solution into rats for a 15-week period
produced splenomegaly with anemia, hyperplasia of the bone marrow elements,
reticulocytosis, leukopenia, varying thrombocytopenia, ascites, and infiltration
of the spleen, liver, and kidneys with storage-cell macrophages.(134) Renal injury
was present in rats administered 10 x 50 mg ip injections of MC over a 30-day
period (13’) Splenectomy in the rat prior to administration of MC prevented the
development of hematological abnormalities.(‘34~135)

Absorption, Distribution, Metabolism, and Excretion

The absorption, distribution, metabolism, and excretion of orally ingested

cellulose and its derivatives have been studied extensively. The published litera-
ture prior to 1974 indicates that cellulose derivatives pass unchanged through
the gastrointestinal tract following oral administration in rats, dogs, and man.
Rabbits apparently digest about 50% of the ingested amount of CG, although this
has been attributed to bacterial action present only in herbivorous animals.(‘,*)
Kitagawa et al. (13’) studied the fate of 14C-HPC (labeled in the hydroxypropyl
group) orally administered to rats. The 14C-HPC and nonradioactive HPC were
suspended in 15% gum arabic solution and administered by stomach tube to
20 COSMETIC INGREDIENT REVIEW

male and female rats at a dose of 1.3 g/kg. Radioactivity was measured in the
urine, feces, bile, tissues, and gastrointestinal tract. The radioactivity was almost
completely excreted in the feces, which, at 96 h, accounted for 97.3 and 96.8%
of the radioactivity ingested by the males and females, respectively. A combined
total of 99.9 and 98.3% of the radioactivity was excreted in the urine and feces
(at 96 h) of the males and females, respectively. The radioactivity in the bile and
tissues was very low; the highest level was found in the liver, although only trace
amounts remained at 72 h. Radioactivity in the gastrointestinal tract decreased to
1.5% after 48 h and was less than 0.05% after 72 h. Urine metabolite radioactiv-
ity was insufficient for complete analysis. It was concluded that HPC is poorly
absorbed from the gastrointestinal tract in the rat.
Another metabolism study was conducted in which 14C-HPC was orally ad-
ministered to 2 male and 2 female rats at doses of 250 mg/kg and 1000 mglkg.
Radioactivity was measured in the expired air, urine, feces, blood, liver, kidneys,
and gastrointestinal tract. No radioactivity was detectable in the expired air or
blood. The urine contained about 3.2% of the total radioactivity at 24 h. The fe-
ces contained 96-100.5% of the radioactivity at 96 h, with the greatest amount
being excreted between 12 and 48 h. The liver, kidneys, and gastrointestinal
tract contained O-0.25% of the administered doses.(‘38)
A distribution study was conducted in rats with 14C-CG. Five male rats re-
ceived 0.4 g 14C-CG in 18 ml of water by stomach tube; a similar dose of unla-
beled CG was administered to another 5 rats as controls. Urine was collected for
44 h, at which time the animals were killed and samples were taken of the stom-
ach, small and large intestine, liver, and kidneys. Almost all of the radioactivity
was found in the large and small intestine; activities in the urine, kidneys, and
liver were comparable to controls.(139)

ANIMAL TOXICOLOGY

Acute Toxicity

Oral
An acute oral LDso test was conducted on a 50% (wt/vol) solution of HEC in
corn oil. Doses of 6834, 10250, 15380, and 23070 mg/kg were administered by
oral intubation to groups of 4 rats. After a 16day observation period, all rats
were necropsied. No deaths or gross pathological changes were noted. Reac-
tions included hypoactivity and ruffed fur in all groups and diarrhea for 2 days in
rats of the highest dose group(140) (Table 3).
In another test for oral toxicity, a single dose of HEC in a 10.9% aqueous dis-
persion was administered to 10 male albino rats, giving an effective dose of 8.7
g/kg body weight. This was the largest single dose possible due to the limitation
of the viscosity of HEC water dispersions. No effects on appetite and growth, no
deaths, and no lesions were noted during the 14day observation period(14’)
(Table 3).
Low, middle, and high viscosity HPC solutions (aqueous) had oral LDsos > 5
g/kg in mice and rats. (14*) No mortalities resulted when rats were administered
HPC in gum arabic solution in as large a dose as possible, considering their gas-
ASSESSMENT: CELLULOSE POLYMERS 21

tric capacity. The acute oral LDso was defined as > 15 g/kg HPC.‘143’ Similarly,
no deaths occurred when HPC was administered as a lb'/, aqueous solution to
rats at an oral dose of 10.2 g/kgc144)(Table 3).
A conditioning polish remover containing 0.7% HPC had an acute oral LDso
of 10.1 ml/kg (or 8.2 g/kg) in rats(14’) (Table 3).
HPMC administered to rats in single oral doses of up to 4 g/kg produced no
toxic effects(1,146) (Table 3).
CMC administered to rats, rabbits, and guinea pigs in single oral doses of 5
g/kg produced no toxic effects. (I) A cosmetic eye makeup product containing
0.605% CMC had an oral LDso > 50 g/kgc14’) (Table 3).
CG administered to rats, rabbits, and guinea pigs in single oral doses of 3 g/
kg produced no toxic effects. (1*148)Acute oral LD,,s of CG were approximately
27 g/kg in rats and 16 g/kg in guinea pigs.(1.149,150)The LD,,s of various cosmetic
products containing 0.3-3.0% CG are reported in Table 3.

lntraperitoneal
No deaths or toxicity resulted from single ip injections of 2.5 g/kg HPC in
male mice (10) and male and female rats (10 of each sex).‘142)
A 5% MC solution injected ip into mice (18 groups of 10 males) gave an LDo
of 147 ml/kg and an ED0 of 1.0 ml/kg.(‘)
HPMC injected ip into 138 mice had an approximate LDso of 5 g/kg.(‘)
Usmanov et al. (156) reported that CMC was essentially nontoxic when in-
jected ip into mice. CMC particles were found in the pulmonary reticuloendo-
thelial cells 48 h after 6 rats were injected ip with 1 ml of a 1.6% CG solution.“)

Intravenous
No deaths or other toxic effects resulted when HPC was injected iv at a dose of
0.5 and 0.25 g/kg in mice (10 males) and rats (10 of each sex), respectively.(‘42)
Rabbits injected iv with 10 mg/kg MC developed leukopenia; however, in-
jections of lo-100 ml/kg of a 1% MC solution had no effect on blood pressure or
respiration.“’ Transient hyperlipemia and small atherosclerotic lesions of the
aorta were noted in 3 of 8 surviving rabbits injected iv with 25 ml of a 1.2% (wt/
vol) aqueous solution of MC or 50 ml (divided into three injections) of a 0.5%
(wt/vol) saline solution of MC.(“‘)
H ueper (136~158~159)
reported that iv injections of MC administered to dogs and
rabbits caused hematological alterations and retention and accumulation of MC
in the liver, spleen, lymph nodes, kidney, and vascular walls. He also found that
single iv doses of CMC caused only mild transitory shifts in the cellular elements
of the blood of the treated dogs.(160)
Usmanov et aI. reported that the iv toxicity of CMC in mice was strongly
related to its degree of substitution, degree of polymerization, and distribution
range. Increasing the degree of substitution increased acute toxicity, although
not proportionally.

Subcutaneous
Usmanov et al.(ls6) reported that CMC was essentially nontoxic to mice
when injected subcutaneously.
TABLE 3. Acute Oral Toxicity

No. of LDS0
ingredient Animal animals We’ Comments Reference

HEC 50% solution Rat 4 per group >23.07 Ruffed fur and hypoactivity; some diarrhea at high 140
in corn oil dose level
HEC 10.9% in aque- Rat 10 >a.7 No toxic effects 141
ous solution

HPC in aqueous Rat 60 >5 Light ataxia and inactivity on first day only; no deaths 142
solution
Mouse 30 >5 Light ataxia and inactivity on first day only; no deaths 142
HPC in go 1 arabic Rat 30 >15 No deaths 143
solution
HPC 10% in aque- Rat 25 >10.2 No deaths; some lassitude on first day 144
ous solution
HPC 0.7% in condi- Rat 40 8.2 145
tioning polish
remover

HPMC Rat 11 >4 No toxic effects 1

HPMC 5% in aque- Rat 15 >l No toxic effects 146
ous solution

CMC in olive oil Rat Unspecified >5 No toxic effects

and aqueous gum Rabbit Unspecified >5 No toxic effects
arabic Guinea pig Unspecified >5 No toxic effects
 Lb
w
E
CMC 0.605% in eye Rat
E
10 >50 Two deaths due to mechanical obstruction of intes- 147
product tine at high dose; no toxic effect in others z. .
n
CC 3% in aqueous Rat Unspecified >3 No toxic effects 1 =!
solution Rabbit Unspecified >3 No toxic effects 1 E
Guinea pig Unspecified >3 No toxic effects 1
CC 2.5% in aque- Rat 12 >3 Ruffed fur and hypoactivity; no deaths 148 K
m
ous solution
CC Rat Unspecified 27 LDm = 40 g/kg; no effect level of 20 g/kg 1
g
CC 1 g in 2.5 ml Rat 40 27 - 149
olive oil 3

CC Guinea pig Unspecified 16 LDo = 10 g/kg 1 i

CC 1 g in 2.5 ml Guinea pig 30 16 - 150
olive oil
CC 3.0% in wrinkle- Rat 5 >15 No deaths, no toxic effects; considered nontoxic by 151
smoothing cream ingestion
CC 1.1% in medi- Rat 5 >lO No deaths, no toxic effects; considered nontoxic by 152
cated lotion ingestion
CG 1.0% in paste Rat 5 >15 No deaths, no toxic effects; considered nontoxic by 153
mask ingestion
CC 0.5% in liquid Rat 10 >5 No deaths, no toxic effects 154
eye liner
CG 0.3% in mois- Rat 10 > 7 ml/kg No deaths, no toxic effects 155
turizer
24 COSMETIC INGREDIENT REVIEW

Inhalation
An acute inhalation study was conducted on HEC using 2 rats, 2 mice, and 2
guinea pigs. The animals were exposed to 0.19 mg HEC/L air for 6 h in a 70-L
chamber. All animals were necropsied after a S-day observation period. No mor-
talities, unusual behavioral reactions, significant body weight, or gross pathologi-
cal changes were noted.““”

Dermai
HPC, 0.8% in an antiperspirant, was tested for dermal toxicity. A single oc-
clusive patch containing 5.0 g/kg HPC was applied to each of 6 rabbits. No
deaths occurred and no dermal irritation or gross effects were noted at the 14-
day necropsy. The product was considered nontoxic by a single dermal expo-
sure at a dose 500 times the expected human exposure.(‘621

Irritation

Ocular
HEC was evaluated for ocular irritation in two Draize tests. Each test was
conducted on 8 rabbits: 4 rabbits had their eyes rinsed for 2 min after a 1-min ex-
posure period, and 4 had unrinsed eyes. In the first test, 100 mg of 100% HEC
was instilled into each rabbit eye. A dose of 0.1 ml of a 2% wt/vol solution of
HEC in water was administered in the second test. Eyes were scored according
to Draize at 1, 24, and 72 h and 7 days. Mean scores at 1 h for the rinsed and un-
rinsed eyes of those rabbits receiving 100% HEC were 4.0 and 10.0 (max = 1 lo),
respectively; means at all subsequent readings were 0. Those rabbits receiving
2% (wt/vol) HEC had l-h means of 2.5 and 2.0 for the rinsed and unrinsed eyes,
respectively; means at all subsequent readings were 0. Thus, HEC was initially
minimally irritating to rabbit eyes; however, all irritation had cleared by
24 h(163.164)(Table 4).
Laillier et al.(‘ss) developed an objective method to measure cornea1 and
conjunctival edema in the rabbit by determination of dry tissue weight and to
measure vascular leakage in the conjunctiva and aqueous humor by dye diffu-
sion. Aqueous solutions of HEC in concentrations of 0.5 and 1 .O%, along with
other organic solvents, were tested in single and repeated topical applications.
Four albino rabbits were used for each solution. Applications of 0.1 ml were in-
stilled into the conjunctival sac of both eyes of each rabbit 1, 3, 6, 7, and 13
times over the following oeriods: 2, 4, 7, 26, and 50 h. The rabbits were also
given 50 mg/kg Evans blue dye solution by injection into the marginal ear vein
1 h after the last instillation of the test solution. The content of Evans blue in
aqueous humor and conjunctiva M/as assayed 1 h after the dye injection. Assays
were conducted to evaluate the cornea1 and conjunctival edema; tissues, cor-
neas, and conjunctivae were dried by overnight immersion in acetone and sub-
sequent storage over silica gel in a vacuum desiccator for 24 h.
After one instillation, 0.5% HEC had no significant effect on the eyes; 1%
HEC was one of the lowest ranking compounds causing some irritation. Follow-
ing repeated administration, both HEC solutions were given the lowest irritancy
ranking. Statistically significant findings included: increase in fig Evans blue/g dry
ASSESSMENT: CELLULOSE POLYMERS 25

weight of conjunctivae after 6 instillations of 0.5% HEC, increase in pg Evans

blue/ml aqueous humor after 3, 7, and 13 instillations of 0.5% HEC, increase in
pg Evans blue/ml aqueous humor after 1 instillation of 1 .O% HEC, increase in pg
Evans blue/g dry weight of conjunctivae after 3, 6, and 13 instillations of 1 .O%
HEC, and a decrease in percent dry weight of conjunctivae after 3 administra-
tions of 1 .O% HEC(16’) (Table 4).
An ocular irritation test was conducted on HEC (2%; two samples), HPC
(2%), MC (2%; three samples), and CC (1, 4, and 10%). Aqueous solutions of
each cellulose derivative were prepared and preserved with sodium paraben
(0.15%) and propylparaben (O.OS”/,). Groups of 6 male albino rabbits were ad-
ministered 0.1 ml of each solution in the conjunctival sac of the right eye, the
other eye serving as a control. Readings were taken at 1 h, 1, 2, 3, 4, and 7 days
after administration; observations were made with the unaided eye, ophthalmo-
scope, and/or slit lamp. Reactions were graded on a scale of 0 to 110 and the
Acute Ocular Irritation Index (AOII) was calculated for each sample. The AOIls
ranged from 5.33 to 10.50 (max = 110). No lesions of the ocular mucous mem-
brane were noted. The investigators concluded that HEC, HPC, MC, and CG,
under these conditions, were slightly irritatingt9) (Table 4).
HPC (50 mg) was instilled into both eyes of 2 rabbits to evaluate ocular irri-
tancy. One eye of each animal was rinsed after a 1-min exposure. The eyes were
scored according to Draize; all eyes had a score of 0 by 24 h. Slight irritation was
noted in both unrinsed eyes at 1 h(‘66) (Table 4).
The Draize method was also used to evaluate the irritancy of 0.5 and 1 .O%
aqueous solutions of HPC in rabbits. A 0.1 ml sample of each solution was in-
stilled into one eye of each of 3 rabbits; the other eye received a saline solution
as a negative control. Isopropyl alcohol was administered to 3 rabbits as a posi-
tive control. The Draize score for each HPC solution was 0; the positive control
had a score of 22.7. HPC was considered nonirritating(“0) (Table 4).
A 5 mg HPC-soluble ocular insert was evaluated for irritation, ease of inser-
tion, and retention time in both eyes of 12 beagles. Each dog received an insert
at three different conjunctival sites for S-day periods. Each test period was sepa-
rated by 2 rest days. The inserts in the conjunctival cornices did not irritate the
cornea and conjunctiva. Conjunctival hyperemia and chemosis were observed
in 5 eyes with inserts beneath the nictitating membrane; however, this was at-
tributed to the trauma caused by the difficult placement of these inserts(16’)
(Table 4).
MC, in a l-2% solution, failed to produce irritation to the conjunctival
membrane of a rabbit.“’
HPMC was evaluated for ocular irritancy in 1 rabbit. A 0.1 mg sample of
HPMC (solid) was instilled into one eye for a 30-set exposure. The eye was ‘then
rinsed with water for 2 min. The other eye then received a similar sample but
was not rinsed. Slight conjunctival irritation was noted after application. The
eyes were completely healed within 48 h. It was concluded that the solid mate-
rial may cause slight transient eye irritation(168) (Table 4).
CG was evaluated for ocular irritancy in 2 Draize tests. A 0.1 mg sample of
CG (in water) was applied to the left eye of 6 rabbits in the first test, and a 0.01 g
sample (solid) was similarly applied in the second test. None of the treated eyes
was rinsed and the right eye of each animal served as the control. Eyes were
scored at 1 min, 1,24, and 72 h, and 4 and 7 days. All eyes had a score of 0 (max
 w

TABLE 4. Ocular Irritation

ingredient Animal No. of animals Method Results Reference

HEC 100% Rabbit 8-4 rinsed Draizea Scores of 4 and 10 for the rinsed and 163
(100 mg) 4 unrinsed unrinsed eyes, respectively, at 1 h; all
subsequent scores - 0; nonirritating
HEC 2% in aqueous Rabbit 8-4 rinsed Drake Scores of 2.5 and 2.0 for the rinsed and 164
solution 4 unrinsed unrinsed eyes, respectively, at 1 h; all
subsequent scores = 0; nonirritating
HEC 0.5 and 1.0% Rabbit 8 Objective method using Low irritancy after single and repeated 165
in aqueous solution dry tissue weight and administration
dye diffusion
HEC 2% in aqueous Rabbit 6 Official French method AOllsb of 6.17, slightly irritating 9
solution (2 samples) 6 7.50, slightly irritating

HPC 100% (50 mg) Rabbit 2 - both eyes Draize Slight irritation in unrinsed eyes at 1 h; all 166
treated eyes with score of 0 at 24 h
1 rinsed
1 unrinsed
HPC 2% in aqueous Rabbit 6 Official French method AOII of 7.33, slightly irritating 9 8
solution
110 5
HPC 0.5 and 1.0% Rabbit 6 Draize Total score of 0 for each solution;
in aqueous solution nonirritating E
HPC 5 mg Beagle 12 Soluble ocular inserts Nonirritating 167 z

52
MC 2% in aqueous Rabbit Official French method AOIls of 6.83, slightly irritating 9
i
solution (3 samples) 8.17, slightly irritating
;;I
10.50, slightly irritating
1 3
MC l-2% solution Rabbit No irritation
E
<
;
s
HPMC 100% Rabbit 1 -both eyes Single instillation Slight conjunctival irritation noted after 168
(0.1 ms) treated application; eyes healed in 48 h; con-
1 rinsed cluded that solid material may cause
1 unrinsed slight transient eye irritation

CC 1, 4, and 10% in Rabbit Official French method AOIls of (1%) 5.33, slightly irritating 9
aqueous solution (4%) 7.83, slightly irritating
(10%) 6.17, slightly irritating
CG 0.1 mg in aque- Rabbit Draize All eyes had score of 0 by day 3 169
ous solution
CG 100% (0.01 g) Rabbit 6 Draize All eyes had score of 0 by day 4 170
CC 3.0% in wrinkle- Rabbit 6 Modified Draize Average irritation score at day 1 = 0; 171
smoothing prepa- nonirritating
ration
CC 1.1% in a medi- Rabbit 6 Modified Draize Average irritation score at day 1 - 1; 172
cated lotion day 2 = 0; minimally irritating
CC 1 .O% in paste Rabbit 6 Modified Draize Average irritation score at day 1 = 0; 173
mask nonirritating
CC 0.5% in liquid Rabbit 9-3 rinsed Draize No ocular reactions; nonirritating with or 174
eyeliner 6 unrinsed without rinse
CG 0.3% in mois- Rabbit 6 Single instillation Slight conjunctival redness noted after 1 h, 155
turizer but clear by 24 h; no effect on cornea1
and iridial membranes

CMC 0.605% in eye Rabbit 6 Single instillation 2/6 had score of 1 (max = 4) at 24 and 48 175
makeup product h; all 0 at 72 h; nonirritating

aMaximum score = 110

bAOll, acute ocular irritation index; max = 110.

Y
28 COSMETIC INGREDIENT REVIEW

= 110) by 3 and 4 days in the first and second tests, respectively(16v~‘70) (Table 4).
Various cosmetic products containing CG or CMC ranging in concentrations
of 0.3 to 3.0% were nonirritating to minimally irritating in rabbit eyes. Specific
results are given in Table 4.

Dermal
A primary skin irritation test was conducted on HEC (2%; two samples), HPC
(2%), MC (2%; three samples), and CG (1, 4, and 10%). Aqueous solutions of
each cellulose derivative were prepared and preserved with sodium paraben
(0.15%) and propylparaben (O.O5o/o).Each solution (0.5 ml) was applied on two
patch areas, the right (scarified) and left (intact) flanks of male albino rabbits
(6/group). Patches were occluded for 23 h, removed, and readings (scale of 0 to
8) taken 1 and 48 h later. The Primary Irritation Indices (PII) ranged from 0.04 to
0.21 (max = 8). HEC, HPC, MC, and CG, under these conditions, were nonirri-
tati ngcg) (Table 5).
A cutaneous tolerance test was also conducted on this same group of cellu-
lose solutions. Aqueous solutions of 2% HEC (two samples), 2% HPC, 2% MC
(three samples), and 1, 4, and 10% CG were prepared and preserved with so-
dium paraben (0.15%) and propylparaben (O.OS”/O). Male albino rabbits (31
group) had 2 ml of each solution applied on the clipped right and left flanks.
Each sample was spread uniformly by hand and given a light 30-set massage.
Applications were made five times per week for 6 weeks. Clipping was repeated
as needed each Monday, 6 h prior to application. Daily scorings were taken
prior to each application. Recovery was studied for 7 days after the last adminis-
tration. Two biopsies taken from each rabbit at 6 weeks were examined micro-
scopically. The Mean Maximum Cutaneous Irritation Indices (MMII) ranged from
0 to 1 .OO (max = 8). The investigators classified these samples as well tolerated
and nonirritating to relatively well tolerated and slightly irritating”’ (Table 5).
HEC is used in a thixotropic composition for prophylactic treatment of bo-
vine mastitis. It forms a film on the teat and provides a physical barrier to bac-
teria. When tested on milking cows, no signs of irritation were observed.“76)
Teats of cows protected by a similar composition containing HEC after twice-
daily milking for 8 months also had no signs of irritation(76) (Table 5).
An antiperspirant containing 0.8% of HPC was tested for primary skin irrita-
tion. A 0.5 ml sample of the product was applied with an occlusive 24-h patch to
the clipped intact and abraded skin of each of 6 rabbits. Sites were scored 24
and 72 h after application. A marketed antiperspirant was evaluated as a control.
Plls of 0.0 and 0.2 (max = 8) were obtained on the intact and abraded skin, re-
spectively. The product was considered mildly irritating”“) (Table 5).
HPMC (full strength) was evaluated for skin irritation in 2 rabbits. Ten appli-
cations were made over 14 days to the shaved abdomen of each rabbit. The
treated sites were covered with gauze pads so that contact with the skin was
continuous for 2 weeks. One rabbit received applications with dry solid HPMC,
and the other received HPMC moistened with water. Each rabbit additionally re-
ceived HPMC applications daily for 3 days on an abraded skin site. No skin irrita-
tion was observed from contact with the dry material. The moistened HPMC
produced a slight redness believed to be due to the material sticking to the skin.
There was no evidence of systemic injury. Solid HPMC was essentially nonirri-
tating and not absorbed through the skin in harmful amounts(178) (Table 5).
ASSESSMENT: CELLULOSE POLYMERS 29

A facial cleanser containing 1 .l% HPMC was evaluated for skin irritation in
4 rabbits. A 0.5 ml sample of the cleanser (10% in an aqueous solution) was ap-
plied with a 24-h occlusive patch to the shaved skin of each rabbit on both intact
and abraded sites, Sites were scored according to Draize at 24 and 72 h. The
cleanser gave a PII of 0.6 (max = 8)(‘79) (Table 5).
Application of CG or CMC to the shaved abdominal area of rabbits five times
per week for 4 weeks produced no signs of skin irritation”) (Table 5).
Cosmetic products containing from 0.3 to 3.0% CG or CMC were found
nonirritating to slightly irritating when applied topically to the skin of rabbits (see
Table 5 for specific results).

Mucous Membrane

A moisturizing cream containing 0.3% CG was tested for mucosal irritation

in 6 rabbits. Each rabbit (3 males and 3 females) received a 0.1 ml topical appli-
cation to the genital mucosa. No signs of irritation were noted during the 7-day
study.(155)

Subchronic Toxicity

Oral
Diets containing 0.2, 1 .O, and 5.0% HEC were fed to three groups of 20 rats
for 90 days. Two groups/sex were kept as controls. Feed consumption and
weight gain were monitored weekly; behavior was checked daily. Blood and
urine samples were collected from 5 males and 5 females in each group on days
0, 21, 45, and 90. Necropsy was performed on all animals, and tissues were ex-
amined microscopically from 5 males and 5 females from both control groups
and the 1 .O and 5.0% groups. No significant findings attributable to ingestion of
H EC were noted. (ls4)
HPC (of low substitution) was administered by stomach tube to groups of 5
male and 5 female rats for 30 days. HPC was suspended in 1% gum arabic solu-
tion and administered at doses of 1.5, 3.0, and 6.0 g/kg per day. No remarkable
changes were noted in growth, organ weights, hematological and urinary analy-
ses, or tissue alterations. (143)
The oral toxicity of HPC was evaluated in rats fed a diet containing the cellu-
lose derivative at a concentration of 0.2, 1.0, or 5.0% for 90 days. Each test
group consisted of 5 male and 5 female rats. Control groups received 0.2, 1 .O, or
5.0% cellulose diets. No differences between the control and treated groups
were noted in survival, growth, behavior, food consumption and utilization, he-
matopoietic and urinary function analyses, organ weights and organ weight
ratios, or in the gross and microscopic examination of tissues.(lE5)
No adverse effects were noted in chicks fed a diet containing 2% MC for 20-
21 days.“)
No toxic effects were observed in rats given 0.5 g/kg MC (method unspeci-
fied) for 4 weeks. Rats ingesting MC at a dose of 11.4 g/kg per day for 95 days
had no significant pathological changes; however, growth of females was de-
creased about 14%, apparently due to a decrease in food intake. Growth of
males was normal. Similarly, rats fed a 50% MC diet for 90 days had significant
 r;,

TABLE 5. Skin Irritation

No. and type

ingredient of animal Method Results Reference

HEC 2% in aqueous 6 rabbits 23-h occlusive patch on intact and PIIsa of 0.08, nonirritating 9
solution (2 samples) 6 rabbits abraded skin 0.13, nonirritating
HEC 2% in aqueous 3 rabbits Repeated applications 5 times per MMllsb of 0.34, nonirritating and well 9
solution (2 samples) 3 rabbits week for 6 weeks tolerated
1 .OO, slightly irritating and rela-
tively well tolerated
HEC in thixotropic cow Repeated application to the teat up to No irritation 76,176
composition 2 times daily for 8 months

HPC 2% in aqueous 6 rabbits 23-h occlusive patch on intact and PII of 0.13, nonirritating 9
solution abraded skin
HPC 2% in aqueous 3 rabbits Repeated applications 5 times per week MMII of 0.67, slightly irritating and rela- 9
solution for 6 weeks tively well tolerated
HPC 0.8% in an 6 rabbits 24-h occlusive patch on intact and Plls of 0.0 (intact) 177
antiperspirant abraded skin 0.2 (abraded), considered mildly
irritating

MC 2% in aqueous 6 rabbits 23-h occlusive patch on intact and Plls of 0.04, nonirritating 9
solution (3 samples) 6 rabbits abraded skin 0.08, nonirritating
8
6 rabbits 0.21, nonirritating
MC 2% in aqueous 3 rabbits Repeated applications 5 times per week MMlls of 0, nonirritating and very well
9 g
solution (3 samples) for 6 weeks tolerated
3 rabbits 0.34, nonirritating and well toler- 5
rated
0.67, slightly irritating and rela- z
3 rabbits
tively well tolerated g
u
;
HPMC 100% 2 rabbits 10 applications over 14 days for contin- No irritation noted with dry solid; moist-
178 5
uous 2 week contact on intact skin; ened application caused slight redness;
3 daily applications on abraded skin no systemic injury; considered essentially R
<
nonirritating ;
g
HPMC 1 .l % in facial 4 rabbits 24-h occlusive patch on intact and PII of 0.6; essentially nonirritating
cleanser (tested 10% abraded skin
in aqueous solution)

CC 1, 4, and 10% in 6 rabbits 23-h occlusive patch on intact and Plls of 0 cl%), nonirritating
aqueous solution 6 rabbits abraded skin 0.08 (4%), nonirritating
6 rabbits 0 (1 O%), nonirritating
CC 1, 4, and 10% in 3 rabbits Repeated applications 5 times per week MMlls of 1 .OO (l%), slightly irritating and
aqueaus solution for 6 weeks relatively well tolerated
3 rabbits 0.67 (4%), slightly irritating and
relatively well tolerated
3 rabbits 0.34 (lo%), nonirritating and well
tolerated
CC unspecified Rabbit Repeated applications 5 times per week No irritation
concentration for 4 weeks
CC 3.0% in wrinkle- 9 rabbits 24-h occlusive patch to intact skin AIS = 0, nonirritating 180
smoothing prepara-
tion
CC 1 .l% in medi- 9 rabbits 24-h occlusive patch to intact skin AIS = 0.67, slightly irritating 181
cated lotion
CC 1.0% in paste 9 rabbits 24-h occlusive patch to intact skin AIS = 0.17, minimally irritating 182
mask
CC 0.3% in moistur- 3 rabbits Daily application for 4 days PII of 1.6, slight erythema developed and 55
izing cream persisted for 7-day period; 1 rabbit with
slight edema

CMC 0.605% in eye 6 rabbits 24-h open patch for 3 consecutive days No reactions; nonirritating 83
makeup to abraded skin

aPll, Primary Irritation Index (max - 8)

bMMII, Mean Maximum Cutaneous Irritation Index (max - 8)
cAIS, Average Irritation Score (max - 4)
32 COSMETIC INGREDIENT REVIEW

growth depression. This was attributed to the lack of nutrition in a “bulk”-pro-

ducing diet and not to any toxic effect.“)
Dogs fed up to 100 g MC daily for 1 month had no toxic effects.“)
HPMC and MC were evaluated in a go-day feeding study in rats and beagle
dogs. Groups of 10 male and 10 female rats received diets containing 0, 1, 3, and
10% MC or HPMC with a nominal viscosity of 10 cp as well as 0, 3, and 10% MC
or HPMC with a nominal viscosity of 4000 cp. Groups of 2 male and 2 female
beagle dogs received diets containing 0, 2, and 6% HPMC with a nominal vis-
cosity of 10 cp. No evidence of toxicity was observed in rats or dogs as judged by
mortality, body weights, feed consumption, urine analyses, hematological evalu-
ations, serum components values, organ weights, or gross or microscopic altera-
tions. (ls6)
HPMC, in two studies, was fed to rats for 90 days at doses ranging from 0.3
to 20% in the diet. Moderate growth retardation was noted in the males fed the
10 and 20% diets in both studies; the females (one study only) fed the 20% diet
also showed this growth retardation. A decrease in feed efficiency was noted
with the 20% diet in both sexes. In one study, 6 of the 20 rats fed the 20% HPMC
diet died of undetermined causes. No lesions were seen in any tissue from these
rats.“)
Groups of 20 rats were fed HPMC at concentrations of 0, 2, 10, and 25% for
30 days. The highest dose produced weight loss, early deaths, and severe diar-
rhea. Urinary and hematological values were normal except for a decreased red
blood cell count in the high-dose group. Organ weights were normal, and no le-
sions were found.“)
Rabbits (6 per group) fed HPMC for 30 days at concentrations of 0, 2, 10,
and 25% had no toxic effects. Urinalyses and organ weights were normal, and
no lesions were observed.“)
Two dogs were fed 25 or 50 g HPMC daily for 30 days. The dog fed 50 g
HPMC had weight loss, diarrhea, and anemia. Urinalyses, organ weights, and or-
gans were normal in both dogs.“)
HPMC of low viscosity was evaluated for toxicity in rats and dogs. Groups of
15 male and 15 female rats and groups of 4 male and 4 female beagle dogs were
fed diets containing 0, 1, or 5% HPMC for 90 days. No significant toxic effects
were noted with respect to mortality, body weights, feed consumption, urinaly-
ses, hematological and clinical chemistry values, and necropsy and histopatho-
logical examinations.(‘87)
No adverse effects were noted in chicks fed a diet containing 2% CG for 20
days. (‘)
No toxic effects were noted in rats fed 0.3 or 0.5 g CG daily for 2 months or
in rats fed a diet containing 14% CG for 5 weeks. Rats fed a diet containing either
20% CG or CMC for 63 days also had essentially no toxic effects. A slight de-
crease in growth was observed in the rats receiving 20% CG, although this was
attributed to a decrease in nutrient food intake resulting from the bulkiness of
the diet.“’
Five dogs were given doses of CG increasing from 12.5 to 31 to 47 mg/kg
daily over a period of 3-4 months. No gross pathological changes were ob-
served. Uptake of CG into the reticuloendothelial cells of the aorta was observed
at microscopic examination.“’
ASSESSMENT: CELLULOSE POLYMERS 33

Rats were fed a hypercholesterolemic diet both with and without 5% CMC
for 8 or 14 days in order to evaluate the hypocholesteroiemic effect of CMC.
CMC depressed plasma and liver cholesterol concentrations compared to con-
trols; however, it did not alter cholesterol absorption from the gut.(‘)

Intravenous
HEC (three viscosity grades) was injected iv into groups of 2 dogs without
producing any acute or serious reactions. All dogs received five injections per
week of an isotonic HEC solution for 6-l 2 weeks. Concentrations of HEC admin-
istered ranged from 2.3 (high-viscosity solution) to 10.0% (low-viscosity
solution). The high-viscosity solution produced marked anemia, leukopenia, and
increased sedimentation rate and plasma viscosity. The medium-viscosity solu-
tion produced the most pronounced hemodiluting effect and an increased sedi-
mentation rate. No treatment-related lesions were observed in the high- and
medium-viscosity groups. HEC storage in the hepatocytes and the glomerular
endothelial cells, as well as atheromatous and fibrous intimal lesions and medial
degenerations and calcifications, were most extensive in dogs of the low-viscos-
ity group. These reactions were entirely absent in the high-viscosity group.(ls8)
Hueper”“‘) found that repeated iv doses of CMC to dogs resulted in a de-
crease in blood hemoglobin and an increase in sedimentation rate. CMC was
stored in the Kupffer cells, the reticular cells of the spleen, the endothelial cells
of the glomeruli, and on the walls of the aorta and its branches.

Dermal
A wrinkle smoother product containing 3.0% CG was evaluated for dermal
toxicity in rats. Fifteen rats (males and females) received a daily dose of 886 mg/
kg (0.9 ml/kg) of the product 5 days per week for 13 weeks. This was a dose set at
100 times the average daily human use level. Control groups consisted of un-
treated rats and rats treated with ethanol. Each dose was applied by inunction to
an anterior dorsal shaved site on each rat. The product was wiped off 1 h after
application because the active agent, sodium silicate, was a known irritant. No
significant adverse effects were noted in mortality, body weights, hematological
values and urinalyses, organ weights, and gross and microscopic examination.
Scattered transient minimal skin irritation was noted in most test animals during
weeks 2 through 6. The investigators concluded that the product was safe for
marketing.(18v)
A lotion containing 1.1% CG was similarly evaluated for dermal toxicity in
rats. Ten male and ten female rats received a daily dose of 2900 mglkg (2.9
ml/kg) of the lotion 5 days per week for 13 weeks. This was a dose set at 100
times the average daily human use level. Control rats were treated with distilled
water. Each dose was applied by inunction to an anterior dorsal shaved site on
each rat. No significant adverse effects were noted in mortality, body weights,
appearance and behavior, hematological values and urinalyses, or gross and mi-
croscopic examinations. The lotion was not systemically toxic and did not pro-
duce any abnormal cumulative dermal effects.(lvO)
34 COSMETIC INGREDIENT REVIEW

Chronic Toxicity

Oral
A 2-year chronic oral toxicity test was conducted by Smyth et al.,(14’) in
which groups of 32 Wistar strain rats, 16 males and 16 females, each received
diets containing 0.2, 1, and 5% HEC. The resulting mean dosages were, respec-
tively, 0.09, 0.41, and 2.31 g/kg per day. Offspring were kept until at least 10 of
each sex representing 10 litters from each dosage group had attained a weight of
40 g. These rats were maintained on the test diet until the end of the study,
bringing the total number of rats for each dosage group to 52. A control group
was maintained on the basic diet, free of HEC. Criteria evaluated included
growth, food intake, life span, frequency of infections, body weights, kidney and
liver weights, number of litters, hematological values, incidence of neoplasms,
and microscopic alterations of numerous organs.
Forty-eight percent of the rats died during the 2-year period; however, the
investigators found “every death was caused by a recognizable factor distinct
from the doses” and that fatalities were evenly distributed over the test and con-
trol groups. The food intake of the rats fed the 5% HEC diet was one-tenth
greater than that of the other groups. Their feces were noted to be almost white
and bulkier than normal due to the large content of undigested cellulose ether.
None of the other criteria evaluated revealed any relationship between dose and
response”41’ (Table 6).
HPC of low substitution was administered to groups of 5 male and 5 female
rats by stomach tube at a daily dose of 1.5, 3.0, or 6.0 g/kg for 6 months. HPC
was suspended in a 1% gum arabic solution, and control groups received a simi-
lar dose of the vehicle. A slight decrease in body weight was observed in the
males and females at 7-8 weeks. Some variations were noted in organ weights
and organ weight ratios; however, these were distributed randomly and did not
have a dose-response relationship. No other significant effects were observed in
behavior, feed consumption, hematological values and urinalyses, or in histo-
pathological examinations(‘43’ (Table 6).
In studies conducted prior to 1973, no toxic effects were noted in rats fed up
to 5.0% MC for 184 days or in rats fed 1.8% MC for 8 months”) (Table 6).
MC was also evaluated for toxicity in a 2-year feeding study. Groups of 50
male and 50 female rats were fed diets containing 1 or 5% MC with nominal vis-
cosity of 15, 400, or 4000 cp. Control groups of 40 male and 40 female rats were
fed the basal diet. No evidence of treatment-related effects was observed in mor-
tality, body weights, feed consumption, hematological values, serum compo-
nents values, organ weights, gross and microscopic examinations, or in tumor in-
cidence(186) (Table 6).
In studies conducted prior to 1973, rats were fed diets containing up to 30%
HPMC for periods up to 2 years. No significant toxic effects were noted other
than growth retardation at concentrations of HPMC ranging from 20 to 30%.
This has been attributed to malnutrition due to the nonnutritive bulk content of
this diet. No toxic effects were noted in gross and microscopic pathology. Dogs
fed up to 3 g/kg per day of HPMC also showed no toxic effects”’ (Table 6).
In studies conducted prior to 1973, rats and mice were fed diets containing 0
and 5% CMC for periods of 8 months-l year (rats) and from weaning to death
(mice), No toxic effects were noted”’ (Table 6).
ASSESSMENT: CELLULOSE POLYMERS 35

CG has been evaluated for oral toxicity in rats, mice, guinea pigs, and dogs
in numerous studies prior to 1973. Both rats and dogs were fed diets containing
0.5 and 1.0 g/kg CG for 6 months, whereas guinea pigs were administered this
same dosage for 6 months and 1 year. No toxic effects were observed. Other rats
received a diet containing 5% CG for 8 months; no toxic effects were noted. In
another study, rats and mice were fed diets containing 0, 1, and 10% CG for 104
and 100 weeks, respectively. Deaths in the first 1 l/2 years were due to pulmonary
infection; later deaths were attributed to neoplasms common to aging rats and
mice. There was no indication of CMC absorption or storage. Tumor frequencies
were normal. A retardation in growth was observed in the rats receiving 10%
CG, although it was noted that these rats also had a higher feed intake”’
(Table 6).
In unpublished studies, CG was evaluated for oral toxicity in dogs, guinea
pigs, and rats. Diets containing 2, 5, 10, and 20% CG were fed to groups of 3
mongrel dogs for 6 months. Mortality, body weight, hematological and urinary
parameters were monitored. Those dogs on the 20% diet “starved due to inter-
ference with food intake.” No evidence of other toxic or metabolic effects was
noted’“‘) (Table 6).
Groups of 20 guinea pigs were fed diets containing 0 (15 guinea pigs only),
0.5, and 1 .O g/kg CG for 1 year. No effects were noted in growth or at ne-
cropsy(1v2) (Table 6).
Groups of 25 rats (males and females) were fed diets containing 0, 0.1, 0.5,
and 1.0 g/kg CG for 25 months. No significant differences were noted between
the controls and test animals in urinalyses, hematological values, fertility
(through three generations), or findings at necropsy. No neoplasms were found
in the test rats(‘93) (Table 6).

Sensitization
HPMC was evaluated for sensitization using the Magnusson-Kligman guinea
pig maximization test. Thirty guinea pigs were used: 10 experimental, 10 un-
treated, and 10 positive controls treated with mercaptobenzothiazole. Each ani-
mal received three intradermal injections into the shaven shoulder consisting of
0.1 ml of 50% complete Freund’s adjuvant in saline, 0.1 ml of 1% HPMC in sa-
line, and 0.1 ml of 1% HPMC in 50% complete Freund’s adjuvant in saline. One
week later, the same area was pretreated with 10% sodium lauryl sulfate (SLS) in
petrolatum and occlusively patched for 48 h with 25% HPMC in petrolatum. Fol-
lowing a 2-week rest, a 24-h occlusive challenge patch containing 25% HPMC in
petrolatum was applied to the shaven flank of each animal. The control guinea
pigs also received the challenge aplication. Reactions were scored 24 and 48 h
after patch removal. HPCM did not produce any responses indicative of sensiti-
zation and was considered a nonsensitizer. ‘lv4)
HPMC was further evaluated for sensitization in Hartley albino guinea pigs
by use of a modified Maguire method. Ten male guinea pigs each received a 0.1
ml application to the clipped back of 2% HPMC in aqueous solution. This was
repeated for a total of four applications in 10 days. At the time of the third appli-
cation, a 0.2 ml sample of Freund’s adjuvant was injected intradermally at sev-
eral points adjacent to the insult site. After a 2-week nontreatment period, chal-
lenge applications were made to previously untested sites. Ten guinea pigs were
TABLE 6. Chronic Oral Toxicity

Concentration/dose Length of
ingredient (in diet) Animal, No. administration Results Reference

HEC 0.2, 1, and 5% Rats, 32 per group (16 2 years Mortalities unrelated to HEC administration; 141
equivalent to 0.09, male/l 6 female); off- food intake on 5% diet slighly increased;
0.41, and 2.31 spring were main- feces white and bulky
glkg per day tained on test diet
for a total of 52 rats
per dose

HPC in 1% gum 0, 1.5, 3.0, and 6.0 Rats, 10 per group (5 6 months Slight decrease in body weight at 7-8 143
arabic solution g/kg per day (by male/S female) weeks; no other significant toxic effects
stomach tube)

MC 0, 1.66, 1.66 and Rats, 5 per group (3 184 days Slight increase in feed intake and weight
5.0% groups female/one gain: no gross or pathological effects
group male)
MC 1.8% (in diet and Rats, 80 8 months No toxic effects
drinking water)
equivalent to 436
mg/per rat
MC of nominal vis- 0, 1, and 5% of Rats, 1OO/per group years No toxic effects 186
cosity 15, 400, each viscosity (50 male/SO female)
and 4000 cp
8
g
HPMC 0, 1, 3, 10, and 30% Rats, 20 per group 21 days Marked decrease in growth at 30% level; 1
(10 male/l0 female) 50% mortality at 30% level; slight growth E
decrease in 10% males; no pathological f
effects; malnutrition due to nonnutritive
52
bulk in diet
H PMC 0, 20, and 25% Rats, 20 per group 1 year Growth retardation at both levels; no other 1 i
toxic effects z+
HPMC 0, 1, 5, and 20% Rats, 100 per group years High-dose group showed growth reduction 1
(50 male/50 female) in first year; all others normal; trend E
<
continued in second year; no significant ;
microscopic effects or tumors s
HPMC 0, 0.1, 0.3, 1, and 3 Dogs, 2 per group 1 year No toxic effecs
g/kg per day

CMC 0 and 5% Rats, 25 per group 8 months No toxic effects

(10 male/l 5 female)
CMC 0 and 5% Rats, 10 per group 1 year No toxic effects
(male and female)
CMC 0 and 5% Mice, 5 at 0% From weaning No toxic effects 1
10 at 5 % to death

CC 0, 0.5, and 1 .O g/kg Rats, 100 per group 6 months No toxic effects
per day
CG 0, 0.5, and 1 .O g/kg Guinea pigs, 100 per 6 months No toxic effects
per day group
CC 0, 0.5, and 1.0 g/kg Dogs, 10 per group 6 months No toxic effects
per day
CC 0.5 and 1 .O g/kg per Guinea pigs, 20 per 1 year No toxic effects
day group
CC 0 and 5% Rats, 25 per group 8 months No toxic effects
(10 male/l 5 female)
CG 0, 1, and 10% Rats, 100 per group 2 years Slight growth retardation at 10% level, 1
(50 male/SO female) although they had a higher feed intake;
mortalities in first 1% years due to pul-
monary infection; later deaths due to
neoplasia common to aging animals; no
indication of CMC absorption or storage;
tumor frequency normal
CC 0, 1, and 10% Mice, 100 per group 100 weeks Mortalities in first 1% years due to pul- l
(50 male/SO female) monary infection; later deaths due to
neoplasia common to aging animals; no
indication of CMC absorption or storage;
tumor frequency normal
CG 2, 5, 10, and 20% Dogs, 3 per group 6 months Dogs on 20% diet “starved due to inter- 191
ference with food intake”; no evidence
of other toxic or metabolic effects
CG 0, 0.5, and 1 .O g/kg Guinea pigs, 20 per 1 year No toxic effects 192
per day group
CG 0, 0.1, 0.5, and 1 .O Rats, 25 per group 25 months No toxic effects 193
g/kg per day (male and female)
38 COSMETIC INGREDIENT REVIEW

similarly tested with a positive control. No responses were noted on challenge

with HPMC, whereas the positive controls responded with moderate to severe
redness. The negative response by guinea pigs would indicate that humans
would not be sensitized by HPMC.““)

Phototoxicity

A phototoxicity test was conducted on a mascara containing 0.4% HEC. A

0.25 ml dose of the mascara was applied to the shaved skin of each of 6 albino
rabbits. A positive control group received applications of 8-methoxypsoralen.
The rabbits were then exposed to UV light at a distance of 8 inches from the skin
(some of the sites were covered). No irritation was produced by the mascara at
either the irradiated or nonirradiated sites. The product was nonphototoxic
when compared to the positive control.(196)
A liquid eyeliner containing 0.5% CG was evaluated for phototoxicity in al-
bino rabbits. Two occlusive patches containing samples of the eyeliner were ap-
plied to the shaved back of each of 6 rabbits. One rabbit received two patches of
8-methoxypsoralen as the positive control. After 2 h, one patch on each animal
was removed and the site was irradiated with a Sylvania No. F40-BLB lamp. The
other sites were protected by aluminum foil. The irradiated sites were then re-
patched and covered with an occlusive binder. All patches were removed at
48 h and scored at 49, 72, and 96 h. Nonirradiated sites produced a mean irrita-
tion score of 0.22 (max = 8); irradiated sites had a mean phototoxic irritation
score of 0.39 (max = 8); both were considered minimally irritating. The product
was concluded to be minimally irritating but not phototoxic to the skin of rab-
bits (197)

Teratogenicity/Reproduction Studies

Groups of 1 l-13 mice were injected ip on days 3-7 or 8-12 of pregnancy

with 10 ml/kg physiological saline, sesame oil, 1 or 4% HEC. Teratological effects
were determined on day 19. Fetal resorption was significantly increased by HEC
at both concentrations when administered on days 3-7; there were 18.7 and
43.8% resorptions for 1 and 4% HEC, respectively, compared to 8.3% for the sa-
line control and 5.1% for the sesame oil. Weights of the surviving fetuses in the
4% HEC group administered on days 3-7 were significantly increased. This same
group had 10.20 and 10.53% gross visceral and skeletal deformities, respec-
tively, compared to 1.98 and 1.96% for the saline control, 4.65 and 9.76% for
the 1% HEC solution, and 1.39 and 8.57% for the sesame oil. All groups receiv-
ing the HEC solutions had a lower percentage of fetuses with additional ribs than
the saline control.(198)
Kitagawa et al. (1g9,200)
studied the teratological effects of HPC in both rabbits
and rats. Doses of 0, 200, 1000, and 5000 mg HPClkg per day were administered
by stomach tube to groups of 12, 11, 11, and 12 Himalayan rabbits, respectively,
on days 6-18 of gestation. HPC was suspended in 1% gum arabic solution; con-
trols received 10 mglkg of the vehicle. The low dose represented 10 times the
human use level, and the high dose was the largest amount of substance techni-
cally possible to administer by stomach tube. Cesarean sections were performed
ASSESSMENT: CELLULOSE POLYMERS 39

on the 29th day of gestation. All of the fetuses were examined for skeletal and
organ malformations. No embryotoxic or teratogenic effects were noted, and no
adverse influence on behavior, appearance, and growth of the maternal rabbits
was observed.
Wistar rats received similar doses of HPC, 0, 200, 1000, and 5000 mg/kg per
day by stomach tube on days 7-l 7 of gestation. HPC was suspended in 1% gum
arabic solution; the controls received 62.5 ml/kg of the vehicle. The low and
high doses represented 10 and 250 times the human use level, respectively. On
day 21 of gestation, cesarean sections were performed on 21-24 rats in each
dose group; the remaining 12-l 5 rats in each dose group were allowed to de-
liver spontaneously. Those pups delivered spontaneously were weaned at 28
days, and 2 males and 2 females from each litter were randomly selected for F,
generation reproduction studies. No significant embryotoxic or teratogenic ef-
fects nor abnormalities in fetal skeletal development and F, generation reproduc-
tive abilities were noted.(200)
In two separate studies, three generations of rats were fed basal diets con-
taining up to 5% MC. These rats consumed more feed than the controls and had
increased body weights. No significant adverse effects were noted on reproduc-
tive function. At gross and microscopic examination of the first generation ani-
mals (in one study), no tissue damage was observed.“)
Pregnant rabbits were fed diets containing 0.25-0.5% MC on days 9-16 of
gestation. No teratological effects were noted; however, some fetal toxicity was
observed.‘2)
MC, in corn oil, was administered by intubation to pregnant mice, rats, and
hamsters. Doses of 345 mglkg MC given to mice on days 6-15 of gestation pro-
duced no effects on nidation or maternal or fetal survival. Doses of MC (1600
mglkg per day) similarly administered to mice produced no clear evidence of ter-
atological effects; however, this dose did produce an increase in maternal mor-
tality and number of resorptions and a decrease in pregnancy rate and fetal
growth. These latter effects were attributed to the administration of a dose essen-
tially equal to an LD 5o, even though administered over a period of 10 days. Simi-
lar studies in rats and hamsters, administered doses up to 1320 and 1000 mglkg
per day for 10 and 5 days of gestation, respectively, produced no significant ef-
fects on nidation or maternal or fetal survival. Abnormalities in the soft or skele-
tal tissues of test and sham-treated controls were comparable.(2)
The teratogenicity and toxicity of MC were studied in CD/l mice. Groups of
20 pregnant mice were administered MC doses of 0, 70, 153, 330, and 700 mg/
kg by gavage on days 6-15 of gestation. The high dose was equal to 10% of the
LDso. MC was administered as a 1.2% suspension in corn oil; the negative con-
trol group received an equal volume dose of corn oil, and the positive controls
received 150 mg/kg acetylsalicylic acid. The mice were killed on day 17 of gesta-
tion, and the urogenital tracks were examined at necropsy. Fetal abnormalities
were determined by external, visceral, and skeletal examinations. No significant
teratogenic or toxic effects were noted.““‘)
The teratogenicity and toxicity of MC were similarly studied in Sprague-
Dawley rats. Groups of 20 pregnant rats received MC doses of 0, 120, 260, 556,
and 1200 mg/kg by gavage on days 6-15 of gestation. The high dose was equal
to 10% of the LDso. MC was administered as a 10% suspension in corn oil; the
40 COSMETIC INGREDIENT REVIEW

negative control group received an equal volume dose of corn oil, and the posi-
tive controls received 250 mg/kg acetylsalicylic acid. The rats were killed on day
20 of gestation, and the urogenital tracks were examined. Fetal abnormalities
were determined by external, visceral, and skeletal examinations. No significant
teratogenic or toxic effects were noted.(‘O’)
Three generations of rats were fed diets containing 0, 0.1, 0.5, and 1 .O g/kg
CG. A slight increase in weight was observed in the treated animals. No signifi-
cant adverse effects were noted in fertility, gross or microscopic lesions, urinaly-
ses, and hematological values.“)
Rats fed 5 ml of a 0.2% solution of CMC on the eleventh day of gestation
showed an increase in resorption rate and in the number of malformed
fetuses. r2)
MC, CG, and CMC have been used as vehicles and negative controls in vari-
ous teratological studies. Concentrations ranged from 0.5 to 1.25% for
MC,(203.204) 0.5 to 2% for CG,(205.206) and 1% for CMC.(207)

MUTAGENICITY AND CARCINOGENICITY

MC (50 pg) was nonmutagenic in the Ames test with Salmonella typhi-
murium strains TA98, TAlOO, TA1535, TA1537, and TA1538, both with and
without metabolic activation.(208)
MC was evaluated for mutagenicity in three different test systems: a host-me-
diated assay (in vitro and in vivo), cytogenetic studies (in vitro and in vivo), and a
dominant lethal assay (in vivo). In the host-mediated assay, no significant in-
crease in mutant or recombinant frequencies was observed when MC was tested
in vitro at a concentration of 10% or in vivo at doses up to 5000 mg/kg (in mice)
using S. typhimurium strains TA1530 and G-46 and Saccharomyces D3, respec-
tively. In the cytogenetic studies, rats administered orally up to 5000 mg/kg MC
had no significant aberrations of the bone marrow metaphase chromosomes. No
significant aberrations were noted in the anaphase chromosomes of human tis-
sue culture cells exposed up to 800 mcglml MC. MC was nonmutagenic in the
dominant lethal assay in rats dosed with up to 5000 mg/kg.(209)
CG was evaluated for mutagenicity in a series of short-term assays using S.
typhimurium strains TAlOO and TA98 and silkworms for mutations, Bacillus sub-
tilis for ret assay (without metabolic activation), and hamster lung fibroblast cells
for chromosomal aberrations (without metabolic activation). Results were nega-
tive for all tests; investigators concluded that CG was nonmutagenic.(2’0)
CMC was nonmutagenic in S. typhimurium strains TAlOO and TA98 both
with and without metabolic activation and in Escherichia co/i strain WP-2 with-
out metabolic activation.(211)
Twenty-five Bethesda black rats were injected subcutaneously with 500 mg
of powdered MC and tissues were examined 2 years later. The tumor incidence
was similar in treated rats and controls.(‘)
Several studies have been conducted to evaluate the effects of MC on rats
transplanted subcutaneously with Murphy-Sturm lymphosarcoma. Intraperito-
neal injections of MC (2 ml of a 2.5% aqueous solution) produced a significant
increase in the percentage of complete tumor regressions. A similar study in rats
ASSESSMENT: CELLULOSE POLYMERS 41

transplanted with Walker tumor 256 gave no indication of beneficial effects due
to MC.“’
Weekly subcutaneous injections of 1 ml of a 2% CMC solution administered
to 30 rats for 73 weeks produced tumors at the injection site in 43% of the ani-
mals. Deposits of CMC were also found at injection sites. The tumors were fibro-
sarcomas. (‘)
CMC has been used as the vehicle and negative control in a bioassay of sele-
nium sulfide. A 0.5% aqueous solution of CMC was administered by gavage to
groups of 50 rats and 50 mice of each sex 7 days per week for 103 weeks. Dose
volumes were 1 ml/kg body weight in rats and 10 ml/kg body weight in mice.(“*)

CLINICAL ASSESSMENT OF SAFETY

Oral Toxicity

The World Health Organization (‘13) has established an acceptable daily in-
take for man of up to 25 mglkg body weight for HPC, HPMC, MC, and CG; this
intake level represents the sum total of modified celluloses.
Single oral doses of MC ranging from 0.6 to 8.9 g have produced only mild
laxative or constipating effects in man. Daily doses of l-6 g MC (max = 6 g for
up to 240 days) were effective in the alleviation of chronic or acute constipation
and produced no evidence of systemic changes or toxicity. Daily doses of 10 g
MC were effective as a laxative.“)
Similarly, CG has been administered orally as a laxative in large doses with
no adverse effects other than mild abdominal discomfort or diarrhea. Twice
daily oral doses of 2-12 g CG produced no serious side effects in 128 subjects.
Daily doses of approximately 10 g CC for 6 months produced no hematological
or toxic effects or mucosal irritation in 22 adults. CG administered as a laxative
to 250 adults over a period of 3 years in twice daily doses of 2-18 g produced no
toxic effects. (I.*)

Ocular Irritation
Three artificial tear solutions, one containing HEC and one containing
HPMC, were tested for dispersion action using 10 subjects. Sterilized fluorescein
was added to a final 2% concentration in each solution. Cornea1 and aqueous
humor fluorescein contents were measured with a slit lamp fluorophotometer.
Four drops of each tear solution, given 5 min apart, were instilled into the con-
junctival sac. Observations were made 1, 2, and 3 h later. Volunteers received at
least two of the tear solutions throughout the experiment, with instillations
spaced several days apart. The tear solution containing HEC gave higher values
of fluorescein uptake by the stroma and anterior chamber than either of the
other solutions. The HEC solution was a 30% more effective delivery system (of
fluorescein). No signs of irritation were reported in this study.t4’)
An eye lotion containing 0.5% CG produced no irritation when used on the
eye. (2’4)
42 COSMETIC INGREDIENT REVIEW

Dermal Irritation and Sensitization

A repeated insult patch test (RIPT) was used to evaluate the irritation and
sensitization of 100 and 5% HEC. Patches were applied to the skin of 50 subjects
for 24 h every other day for a total of 10 applications. Following a 2-week non-
treatment period, challenge patches were applied to adjacent skin sites. All sub-
jects had a score of 0, indicating that 100 and 5% HEC produced no irritation or
sensitization(2’5) (Table 7).
Cosmetic products containing 0.3-l .O% HEC were evaluated by RlPTs in a
total of 708 subjects. These products were nonirritating to mildly irritating and
not-sensitizing. Similarly, in 21-day cumulative irritancy assays, products con-
taining 0.3-0.5% HEC were essentially nonirritating in a total of 52 subjects. Re-
sults of individual studies are presented in Table 7.
Faucher et al.(216) conducted a comparison test of the anti-irritancy effects of
HEC and Polymer JR, an ionic version of HEC. Aqueous solutions containing 2%
of these compounds were applied to the forearm skin on 10 subjects and al-
lowed to dry. Sodium lauryl sulfate (SLS) was subsequently applied to the same
area under occlusive patches for 1 h. A control group, which was not adminis-
tered either polymer, was treated with SLS. This procedure was repeated daily
for 5 days and scoring was made 3 days later. HEC produced some anti-irritant
effects, although Polymer JR clearly had a more potent effect. The average scores
(max = 4) of SLS skin irritation were 3.6, 2.4, and 1.4 for the controls, 2% HEC,
and 2% Polymer JR solutions, respectively. The investigators considered that
these anti-irritancy effects were due to the blocking of skin-reactive sites.
An aqueous solution of 10% HPC was evaluated for irritation and sensitiza-
tion in an RIPT. A series of occlusive patches was applied for 24 h to the same
site on each of 50 subjects every other day for a total of 10 exposures. Following
a 2-week nontreatment period, challenge patches were applied to adjacent sites.
No reactions were observed; all scores were O(‘l’) (Table 7).
Various cosmetic products containing 0.7-0.8% HPC have been evaluated
for irritation and sensitization by single insult patch test (SIPT), RIPT, and 21-day
cumulative irritancy assays in a total of 7, 340, and 27 subjects, respectively.*
These products were essentially nonirritating and nonsensitizing. Results of indi-
vidual tests are presented in Table 7.
Skin tests of MC in 100 men and 100 women were negative for irritation(213)
(Table 7).
Cosmetic products containing MC at concentrations of 0.2 and 0.25% were
evaluated for dermal effects in a controlled use study and an RIPT, respectively.
In the controlled use study conducted on a night cream containing 0.2% MC,
the potential for irritation was no different from a similar control product in the
101 subjects tested. (218)A shampoo containing 0.25% MC was tested as a 10%
dilution by RIPT in 50 subjects. No reactions were observed at induction or chal-
lenge with semi-occlusive patches of the product. Under occlusive conditions,
reactions indicative of primary irritation were observed in 11 subjects at induc-
tion and in 6 subjects at challenge. The investigators concluded that the sample

*These totals may not reflect the actual number of subjects tested as some may have participated in more
than one study.
ASSESSMENT: CELLULOSE POLYMERS 43

was capable of inducing irritation and that the reactions at challenge were also
those typical of irritation and not sensitization(219) (Table 7).
A facial cleanser containing 1.1% HPMC was evaluated for dermal irritation
in a controlled use study. Twenty-five women used the product daily for 14 days;
the majority did not have signs of irritation, and no signs of sensitization were
observed. A few of the irritant reactions were due to the drying effect of the
product(220) (Table 7).
CG was evaluated by patch tests on 200 human subjects; it was neither a pri-
mary dermal irritant nor a sensitizer”) (Table 7).
CG was evaluated for irritation and sensitization in an SIPT with a challenge.
CG (100%) was applied under a lintine disc for 5 days to each of 100 male and
100 female subjects. Three weeks later, a repeat application was made for 48 h.
No reactions were observed after either application of CG(221) (Table 7).
A standard patch test was conducted to evaluate the dermal irritation of 7
urostomal adhesive discs, 1 of which was composed of CG, pectin, and gelatin.
Each disc was applied to the back of each of 74 subjects and allowed to remain
in place for 48 h. All testing was done in duplicate. Observations were made 1
and 24 h after disc removal; sites were scored on a scale of 0 to 3. The disc con-
taining CG was significantly less irritating than the other 6 tested, giving mean
scores of 0.03 and 0.04 at 1 and 24 h, respectively(222) (Table 7).
Various cosmetic products containing 0.2-3.0% CG or CMC have been eval-
uated for irritation and sensitization by SIPT, RIPT, and 21-day cumulative irri-
tancy assays in a total of 158, 1526, and over 45 subjects, respectively.* These
products were nonirritating to slightly irritating and nonsensitizing (Table 7).

Photosensitization

A modified Draize-Shelanski RIPT was used to evaluate the photosensitivity

of a mascara containing 0.4% HEC. A panel of 101 subjects completed the test,
half of whom were classified as having sensitive skin. Occlusive 24-h patches
were applied to different quadrants of the back on each subject on Mondays,
Wednesdays, and Fridays for a total of 10 insults. Two weeks later, a 48-h chal-
lenge patch was applied to an adjacent site. Sites were irradiated with UVA im-
mediately after scoring of the first, fourth, seventh, tenth, and challenge patches.
The UVA light source (-360 nm) was a Hanovia Tanette Mark I Lamp placed at
a distance of 12 inches from the skin for 1 min. Sites were scored 48 h after each
UVA exposure. No reactions were observed in any of the subjects(229) (Table 8).
A conditioning polish remover containing 0.7% HPC and a moisturizer con-
taining 0.25% CG were evaluated for photosensitivity in 101 and 105 subjects,
respectively. Each subject received an occlusive patch on the upper back and
another open patch on the wrist for 48 h. Two weeks later these procedures
were repeated. Upon removal of the latter occlusive patch, each skin site was ir-
radiated for 1 min with a Hanovia’Tanette Mark I lamp emitting UVA of wave-
length 360 nm at a distance of 12 inches from the skin. Sites were scored 48 h

*These totals may not reflect the actual number of subjects tested as some may have participated in more
than one study.
TABLE 7. Clinical Irritation and Sensitization

Compound tested Type of test No. of humans Results/comments Reference

HEC 100% RI PTa 50 All subjects had score of 0; nonirritating and nonsensitizing 215
HEC 5% RIPT 50 All subjects had score of 0; nonirritating and nonsensitizing 215
HEC 1% in hair RIPT with 5% aqueous 54 Total of 35 scores of 1 and 7 scores of 2 (max = 5) during 223
cream rinse dilution induction; 3 scores of 1 at challenge-2 at 24 h, 1 at
72 h; nonirritating and nonsensitizing
HEC 0.75% in hair RIPT insult with 50% 99 Scattered scores of 1 and 1 score of 2 (max - 3) during in- 224
conditioner aqueous dilution, duction; 3 reactions at challenge, but only 1 lasting until
challenge with 25% 48 h; this subject was rechallenged with 25 and 13%
aqueous dilution dilutions and open application-mild erythema was eli-
cited by both dilutions, no response to open application;
mildly irritating under occlusion and nonsensitizing
HEC 0.5% in hair RIPT insult with 50% 99 Scattered scores of 1 and 4 scores of 2 (max = 3) during 225
conditioner aqueous dilution, induction; 9 reactions at challenge, but only 3 lasting un-
challenge with 25% til 48 h; these 3 were rechallenged with 25 and 13%
aqueous dilution dilutions and open application-2 subjects reacted to
both dilutions but only 1 lasted until 48 h, no re-
sponse to the open application; mildly irritating and
nonsensitizing
HEC 0.5% in detang- RIPT with 10% aque- 97 No reactions during induction or challenge; nonirritating 226
ling rinse ous dilution and nonsensitizing
HEC 0.5% in mascara 21-day Cumulative 15 Total composite score of 20.0 (max = 630); essentially 227
lrritancy Assay nonirritating
HEC 0.5% in mascara 21-day Cumulative 15 Total composite score of 14.0 (max = 630); essentially 227
lrritancy Assay nonirritating
HEC 0.5% in mascara Maximization test with 25 All subjects had score of 0 at challenge; nonsensitizing 228
SLSb pretreatment
HEC 0.5% in mascara Maximization test with 25 All subjects had score of 0 at challenge; nonsensitizing 228
SLS pretreatment
HEC 0.4% in mascara RIPT 202, half classified Total of 21 scores of 1 and 1 score of 2 (max = 3) during 229
as having sensi- induction; 3 scores of 1 at challenge, but cleared totally
tive skin by 48 h
HEC 0.4% in mascara 21-day Cumulative 10 Total composite score of 32.73 (max = 630); essentially 230
lrritancy Assay nonirritating
HEC 0.3% in moistur- RIPT 107 Four subjects reacted during induction phase: 2 with f, 1 231
izing cream with score of 1, and 1 with score of 2+ (max - 4); this
last subject showed no irritation when patched on an ad-
jacent site; no reactions at challenge; nonsensitizing
HEC 0.3% in moistur- 21-day Cumulative 12 Total composite score of 48.3 (max = 630); essentially 232
izing lotion lrritancy Assay nonirritating
HEC 2% in aqueous Anti-irritation test with 10 HEC showed some anti-irritancy effects attributed to block- 216
solution subsequent treatment ing of skin-reactive sites
of SLS

HPC 10% in aqueous RIP1 50 No reactions during induction of challenge; all subjects 217
solution had score of 0; nonirritating and nonsensitizing
HPC 0.8% in antiper- SlPTc 7 Slight erythema seen in 3 subjects; slight to distinct dryness 233
spirant in 5 subjects
HPC 0.8% in antiper- RIPT 97 Minimal reactions noted on induction consisting of slight 234
spirant erythema and 1 erythema with edema- not considered
significant; no reactions on challenge; nonirritating and
nonsensitizing
HPC 0.8% in body RIPT 91 Three subjects with doubtful erythema and one with ery- 235
cleanser thema during induction; no reactions at challenge; non-
irritating and nonsensitizing
HPC 0.7% in condi- RIPT (Schwartz-Peck 101 No reactions were observed during induction or challenge; 236
tioning polish re- Prophetic Patch) nonirritating and nonsensitizing
mover
HPC 0.7% in condi- RIPT (Draize-Shelanski) 51 No reactions observed to open patches; three weak reac- 236
tioning polish re- tions noted during occlusive induction period; no
mover reactions on challenge; essentially nonirritating and
nonsensitizing
HPC 0.7% in condi- 21-day Cumulative 27 Product gave a total score (based on 10 subjects) of 21.3 237
tioning polish re- lrritancy Assay (max = 630); essentially nonirritating
mover

MC 100% Patch test (unspecified) 200 No signs of irritation 213

MC 0.2% in night Controlled Use Study, 101 Three complaints of dryness; potential for producing ad- 218
cream 3 weeks verse effects no different from control products
MC 0.25% in RIPT tested as 10% 50 No reactions under semi-occluded conditions; irritation 219
shampoo dilution seen in 11 subjects at induction and 6 at challenge
under occlusive conditions; capable of inducing irritation
but nonsensitizing
TABLE 7. (Continued)

Compound tested Type of test No. of humans Results/comments Reference

HPMC 1.1% in facial Controlled Use Study, 25 Few irritant reactions noted; some due to drying effect of 220
cleanser 2 weeks product; no signs of sensitization

cc ioo4b Patch test (unspecified) 200 No primary dermal irritation; did not appear to be 1
sensitizer
CC 100% SIPT (5 days) with chal- 200 No reactions noted; nonirritating and nonsensitizing 221
lenge
CC in adhesive disc SIPT 74 Significantly less irritating than other discs tested; mean 222
irritation scores of 0.03 and 0.04 (max = 3) at 1 and
24 h, respectively
CC 3.0% in wrinkle- SIPT 15 AlId = 0.17, reference Alls of 0.17, 0.12; no significant dif- 238
smoothing cream ference in irritancy between test and controls
CC 3.0% in wrinkle- RIPT 89 Barely perceptible irritation in 8 subjects, mild in 1, no 239
smoothing cream reactions at challenge; essentially nonirritating and non-
sensitizing
CC 1.6% in RIPT 87 Barely perceptible irritation in 12 subjects, mild in 9 at in- 240
foundation duction; 3 barely perceptible at challenge; nonsensitizing
CC 1.1% in product SIPT 19 All = 0.08; comparable to reference control with All 241
(not specified) = 0.10
CG 1.1% in medi- RIPT 86 Barely perceptible irritation in 3 subjects at induction; no 242
cated lotion reactions at challenge; nonirritating and nonsensitizing
CC 1.1% in medi- 2l-day Cumulative lrri- Not specified No significant difference between test product and com- 243
cated lotion tancy Assay petitive control
CC 1.0% in paste SIPT 19 All = 0.08; significantly milder than competitive control 244
mask with All = 0.65
CG 1.0% in paste RIPT 97 Mild irritation in 1 subject at induction; no reactions at 245
mask challenge; nonirritating and nonsensitizing
CG 0.5% in eyeliner 21-day Cumulative Irri- 17 Mean cumulative irritation score of 2.1 (based on 10 sub- 246
tancy Assay jects) on scale with max - 630; essentially nonirritating
CG 0.5% in eyeliner RIPT (Modified Draize- 209 No reactions at induction; 2 mild reactions at challenge- 247
Shelanski) considered clinically insignificant; nonirritating and
nonsensitizing
CG 0.3% in moistur- 21-day Cumulative Irri- 11 Mean cumulative irritation score of 72 (based on 10 sub- 248
izing cream tancy Assay jects) with max = 630; slightly irritating
CC 0.3% in RIPT (Shelanski-Jordan) 210 One subject had 2+ reactions (max = 4+) to two induc- 249
moisturizer tion patches; another subject had 2+ reaction 78 h after
the 2nd challenge; nonirritating and nonsensitizing
CG 0.25% in SIPT with challenge 105 One weak reaction at induction and no reactions at chal- 250
moisturizer (Schwartz-Peck lenge under occlusive conditions; no reaction to open
Prophetic) induction; nonirritating and nonsensitizing
CC 0.25% in RIPT (Draize-Shelanski) 49 Five subjects with single weak reactions at induction and 250
moisturizer one with weak reaction at challenge under occlusive
conditions; no reactions to open induction; nonirritating
and nonsensitizing
CG 0.25% in product Maximization test with 25 No reactions were noted; nonirritating and nonsensitizing 251
(not specified) SLS pretreatment
CC 0.2% in cleanser 2l-day Cumulative 17 Mean cumulative irritation score of 3.5 (based on 10 sub- 246
lrritancy Assay jects) with max = 630; essentially nonirritating
CG 0.2% in cleanser RIPT (Modified Draize- 209 Two reactions during induction- 1 mild erythema and 1 247
Shelanski) intense erythema and edema; 12 reactions at challenge-
9 mild erythema and 3 intense erythema; these were
attributed to irritation; product considered not a strong
irritant and not a sensitizer
CG 0.2% in makeup RIPT (Modified Draize- 209 Four reactions during induction - 1 mild erythema and 3 247
Shelanski) intense erythema; 1 mild reaction at challenge consid-
ered clinically insignificant; product considered not a
strong irritant and not a sensitizer
CG 0.2% in makeup RIPT 206 No hyperpigmentation or positive skin reactions at chal- 252
lenge; nonsensitizing

CMC 0.605% in eye Maximization test with 50 No reactions were noted; nonirritating and nonsensitizing 253
product SLS pretreatment

aRIPT, Repeated Insult Patch Test.

bSLS, Sodium lauryl sulfate.
CSIPT, Single Insult Patch Test.
dAll, Average Irritation Index fmax - 4).
48 COSMETIC INGREDIENT REVIEW

TABLE 8. Clinical Photosensitization of Cosmetic Products

fngredient tested Type of test No. of humans Results/comments Reference

HEC 0.4% in RlPTa with UVA expo- 101, half clas- No reactions observed 229
mascara sure sified as in any of the subjects;
having sen- nonphotosensitizing
sitive skin

HPC 0.7% in con- SlPTb with challenge 101 No reactions observed; 236
ditioning polish and UVA exposure nonphotosensitizing
remover
HPC 0.7% in con- RIPT with UVA expo- 51 No reactions observed; 236
ditioning polish sure nonphotosensitizing
remover

CC 0.25% in SIPT with challenge 105 One weak response; 250

moisturizer and UVA exposure nonphotosensitizing
CG 0.25% in -RIPT with UVA expo- 49 No reactions observed; 250
moisturizer sure nonphotosensitizing

CMC 0.605% in RIPT with maximization 50 No reactions observed; 253

eye product and UV exposure nonphotosensitizing

aRIPT, Repeated Insult Patch Test.

bSIPT, Single Insult Patch Test.

later; all readings were negative for the polish remover, and one weak response
was seen with the moisturizer’236~250’ (Table 8).
These same two products, the polish remover and the moisturizer, were fur-
ther evaluated for photosensitivity in Draize-Shelanski RlPTs in 51 and 49 sub-
jects, respectively. Each occlusively patched skin site was irradiated for 1 min
after the first, fourth, seventh, and tenth insults, as well as after the challenge
patch. The light source was a Hanovia Tanette Mark I lamp emitting UVA of
wavelength 360 nm and held at a distance of 12 inches from the skin. Each site
was scored 48 h after irradiation; all readings for both products were nega-
tive(236,250) (Table 8).
An eye product containing 0.605% CMC was evaluated for photosensitivity
in a modified maximization test on 50 subjects. Each subject received 6 open
patch inductions over a 3-week period, and an open challenge patch after a
S-day rest. Each site received SLS pretreatment and irradiation at the first, third,
and fifth insults and the challenge. The light source was a Hanovia Tanette Mark
I lamp held at a distance of 12 inches from the skin for 1 min. Sites were scored
48 h after each irradiation; no reactions were noted(253) (Table 8).

Mucous Membrane Irritation

HEC, HPC, MC, CG, and CMC are all used in tampons. Recently, MC and
CMC have been implicated in the development of Toxic Shock Syndrome
(TSS).(254) Tierno et al.(255’ have suggested that the CMC in tampons, as it is de-
graded by enzymes in the vaginal cavity (beta-glucosidase and cellulase), may
become an exogenous source of nutrients for pathogenic organisms.
ASSESSMENT: CELLULOSE POLYMERS 49

Less adverse effects were produced by a suppository base composed of HPC

and carbomer than a comparable base tested in the contact treatment of cervical
cancer lesions. Suppositories were inserted twice weekly for a total of 1 to 14
times. Adverse effects were noted in lo/43 patients using the HPC base com-
pared to 21/42 patients who used the other base. These effects ranged from vagi-
nal and external genitalia erosion to micturition pain to headache, fever, and
nausea. (256)
No evidence of irritation or other adverse effects were noted in the vaginal
mucosa or external genitalia of 134 women treated for vaginal infections with 5 g
of CG (per subject).“)

Inhalation

No inhalation studies have been conducted; however, Clayton and Clay-

tonr257) state that long-term exposure to the dust of cellulose ethers in manufac-
turing operations has not led to any known adverse effects.

SUMMARY

HEC, HPC, MC, HPMC, and CG are modified cellulose polymers derived
from the reaction of the three free hydroxyl groups in the 2-, 3-, and 6- posi-
tions of the anhydroglucose unit of the cellulose molecule. The number of hy-
droxyl groups reacting, as well as the nature of the substituent group, largely
determine the physical properties, particularly solubility, of the product. The vis-
cosity of the final product is greatly affected by the molecular weight of the start-
ing cellulose. All of these cellulose ethers are odorless, tasteless, and very stable
chemically.
The cellulose derivatives are used in a wide variety of cosmetics and toilet-
ries as thickeners, suspending agents, film formers, stabilizers, emulsifiers, emol-
lients, binders, or water-retention agents. Generally, the majority of uses is in
hair products, eye and facial makeups, and skin care preparations. The concen-
tration of use can range up to 10%; however, the celluloses are most frequently
used in concentrations of >O.l-1%. HEC, HPC, MC, HPMC, and CC were used
in a total of 422, 82, 144, 197, and 812 formulations, respectively, in 1981.
The cellulose derivatives are used widely as an ingredient in pharmaceutical
and industrial products. Additionally, all five derivatives are approved as Indirect
Food Additives, and all but HEC are approved as Direct Food Additives. MC and
CG are GRAS food substances.
The cellulose derivatives pass essentially unchanged through the gastrointes-
tinal tract following oral administration to rats, dogs, and man. Rabbits appar-
ently digest about 50% of an ingested amount of CG, although this has been at-
tributed to bacterial action present only in herbivorous animals.
Acute toxicity studies indicate that the cellulose derivatives are practically
nontoxic when administered by inhalation or by oral, intraperitoneal, subcu-
taneous, or dermal routes. Intravenous Injections of HPC in mice and rats and
CMC in dogs were nontoxic; however, iv injections of MC to dogs and rabbits
produced hematological reactions, retention and accumulation of MC in the
liver, spleen, lymph nodes, kidney, and vascular walls, and small atherosclerotic
lesions of the aorta (in rabbits only).
50 COSMETIC INGREDIENT REVIEW

Ocular and dermal irritation studies indicate that the cellulose derivatives
are, at most, minimally irritating to rabbit eyes and nonirritating to slightly irri-
tating to rabbit skin when tested at concentrations up to 100%. No irritation was
noted in the genital mucosae of rabbits treated topically with a moisturizing
cream containing 0.3% CG.
Subchronic oral studies indicate that the cellulose derivatives are essentially
nontoxic when administered to rats, chickens, dogs, and rabbits. Subchronic
dermal studies also indicated that cosmetic products containing CG were non-
toxic in rats.
Subchronic iv administration of up to 10.0% HEC to dogs produced marked
anemia, leukopenia, and increased sedimentation rate and plasma viscosity at
the low dose (high viscosity) and extensive atheromatous and fibrous lesions at
the high dose (low viscosity). The high-dose group gave evidence of HEC storage
by the presence of swollen hepatic, glomerular endothelial, and endocardial
cells. Similar effects were noted in dogs given repeated iv injections of MC and
CMC.
Chronic oral studies indicated that the cellulose derivatives were essentially
nontoxic in rats, mice, dogs, and guinea pigs when administered for periods up
to 2 years. Groups of animals receiving a diet of 20-30’70 cellulose did have
some growth retardation and some deaths; however, these were attributed to
the nonnutritive bulk content of the diet.
HPMC was nonsensitizing in guinea pigs at concentrations up to 25%,
whereas cosmetic products containing HEC and CG were nonphototoxic in
rabbits.
In a teratogenicity study in which pregnant mice were injected ip with 1 or
4% HEC, fetal resorption was significantly increased at both concentrations as
compared with controls, and weights of surviving fetuses in the 4% HEC group
were significantly increased. Other teratogenicitylreproduction studies in which
the cellulose derivatives were administered orally to rats, rabbits, mice, and
hamsters produced no significant teratogenic or reproductive effects.
MC, CMC, and CG were nonmutagenic in various tests both with and with-
out metabolic activation. MC was also nontumorigenic when injected subcuta-
neously in black rats. When injected ip, MC significantly increased the percen-
tage of tumor regressions in mice transplanted with Murphy-Sturm lymphosar-
coma.
The World Health Organization has established an acceptable daily intake
for man of up to 25 mg/kg body weight for HPC, HPMC, MC, and CG; this intake
level represents the sum total of modified celluloses. Daily doses of up to 6 g MC
for up to 240 days have been effective as a laxative and have produced no toxic
effects in man. Similarly, large doses (2-18 g twice daily) of CG have been ad-
ministered orally as a laxative for periods of up to 3 years with no adverse effects
other than mild abdominal discomfort or diarrhea.
No ocular irritation was observed in a clinical evaluation of an eye product
containing 0.5% CG.
The cellulose derivatives (concentrations of 5-lOOO/,) and products contain-
ing these derivatives were nonirritating to mildly irritating, nonsensitizing, and
nonphotosensitizing when evaluated by clinical SIPTs, RIPTs, 21-day cumulative
irritancy assays, and controlled use studies.
ASSESSMENT: CELLULOSE POLYMERS 51

The use of MC and CMC in tampons has recently been implicated in the de-
velopment of Toxic Shock Syndrome. CMC appears to be an exogenous source
of nutrients for pathogenic organisms as a result of enzymic degradation in the
vaginal cavity. Women treated for vaginal infections with CG had no evidence of
vaginal irritation or other adverse effects.
No clinical inhalation studies have been conducted; however, long-term ex-
posure to the dust of cellulose ethers in manufacturing operations has not led to
any known adverse effects.

CONCLUSION

On the basis of the available animal and clinical data presented in this re-
port, the Expert Panel concludes that Hydroxyethylcellulose, Hydroxypropylcel-
lulose, Methylcellulose, Hydroxypropyl Methylcellulose, and Cellulose Gum are
safe as cosmetic ingredients in the present practices of use and concentration.

ACKNOWLEDGMENT

Elizabeth Meerman Santos, Scientific Analyst and writer, prepared the Iitera-
ture review and technical analysis used by the Expert Panel in developing this
report.

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ASSESSMENT: CELLULOSE POLYMERS 55

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ASSESSMENT: CELLULOSE POLYMERS 57

164. CTFA. (January 9, 1975). Submission of unpublished data by CTFA. Rabbit eye irritation study on HEC.
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58 COSMETIC INGREDIENT REVIEW

194. CTFA. (December 5, 1980). Submission of unpublished data by CTFA. Guinea pig maximization test on
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ASSESSMENT: CELLULOSE POLYMERS 59

223. CTFA. (May 1978). Submission of unpublished data by CTFA. Clinical RIPT on HEC. (2-20-90).*
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