Journal of the American College of Toxicology

13(6):418436. Raven Press, Ltd., New York

0 1994 Cosmetic lngrcdient Review

Final Report on the Safety Assessment of

Ethyl Hexanediol'

Abstract: Ethyl Hexanediol is an aliphatic alcohol used as a solvent in a small

number of cosmetic formulations applied to the skin and hair. Animal data
indicate that Ethyl Hexanediol is absorbed through the skin and is metabolized
and eliminated in the urine. Reported oral LDs, values in rats are generally
above 5 gkg. In subchronic oral studies, slight toxicity was manifested as
reduced growth and increased liver weight. Oral delivery of Ethyl Hexanediol
in female rats did show evidence of teratogenicity, but only at levels at which
significant maternal toxicity was seen. Dermal exposure also resulted in de-
velopmental changes, again at levels that also caused maternal effects. Chro-
mosome damage was reported in vitro, but several other genotoxicity assays
were negative. Dermal exposure resulted in no dose-related increases in tumor
incidence in rabbits and mice. In clinical studies, undiluted Ethyl Hexanediol
was a weak irritant and a weak sensitizer. The concentration at which this
ingredient is expected to be used is no greater than 5%. On the basis of the
animal, clinical, and use data presented in this report, it is concluded that Ethyl
Hexanediol is safe as a cosmetic ingredient. Key Words. Ethyl Hexanediol-
Cosmetics.

Ethyl Hexanediol is an aliphatic alcohol used as a solvent in cosmetic formu-

lations. The safety data on this ingredient are presented in this report.

CHEMISTRY
Definition and Structure
Ethyl Hexanediol (CAS No. 94-96-2) is the aliphatic alcohol that conforms to
the following formula (Nikitakis et al., 1991):

CH2CH3
I
CH3CH2CH2-CH-CH-CH20H
I
OH
Other names for Ethyl Hexanediol are ethohexadiol; 2-ethyl-1,fhexanediol; 1,3-
hexanediol, 2-ethyl-; octylene glycol; ethyl hexyleneglycol; 2-ethyl-3-propyl-1,3-

Reviewed by the Cosmetic Ingredient Review Expert Panel.

Address correspondence and reprint requests to Dr. F. A. Andersen at Cosmetic Ingredient Re-
view, 1101 17th Street NW, Suite 310, Washington, D.C. 20036, U.S.A.

418
 ETHYL HEXANEDIOL 419

propanediol; and 3-hydroxymethyl-n-heptan-4-01(Nikitakis et al. , 1991; Sax,

1979; Syracuse Research Corp. , 1982). Materials containing Ethyl Hexanediol are
Lanoquat 1756, Lanoquat 1757, and Unkep U-18(Nikitakis et al., 1991). The
commercial names for this ingredient include Carbide 6-12, Compound 6-12 Insect
Repellent, Repellent 612, and Rutgers 612 (Syracuse Research Corp., 1982).

Chemical and Physical Properties

Ethyl Hexanediol is a colorless, slightly viscous liquid (Hawley, 1971). Its
chemical and physical properties are summarized in Table 1.

Method of Manufacture
Ethyl Hexanediol can be manufactured by hydrogenating butyraldol (Sherman,
1978). It may also be prepared by condensing butyraldehyde with magnesium
aluminum ethoxide and hydrolyzing the resulting ester (Martin and Worthing,
1977).
Ethyl Hexanediol has the following specifcations (Union Carbide Corp. , 1978):
Purity % by wt., min. 97.0
Acidity % by wt., max., as acetic 0.02
Water % by wt., max. 0.05
Color, Pt-Co units, max. 20
Suspended matter Substantially free

Analytical Methods
An analytical method for determining Ethyl Hexanediol in aqueous or alcoholic
solution was developed for studies on the evaporation and absorption of insect
repellents. This method involves reacting Ethyl Hexanediol with concentrated
sulfuric acid and p-dimethylaminobenzaldehydeto obtain a colored compound
that is estimated colonmetrically. Ethyl Hexanediol may be determined on glass,
cloth, and human skin (Bowman et al., 1959).
TABLE 1. Chemical and physical properties of Ethyl Hexanediol
Property Description Reference
~

Molecular weight 146.26 RTECS (1992)

Appearance Colorless, slightly viscous liquid Hawley (1971); Sax (1979)
Odor Odorless Hawley (1971); Sax (1979)
Solubility Soluble in alcohol, ether, and Hawley (1971); Syracuse
chloroform; partially soluble in Research Corp.(1982);
water Hunting (1983)
Specific gravity 0.9422 (20/200C) Hawley (1971)
Boiling point 244°C Hawley (1971)
Melting point - 40°C (sets to glass below this Syracuse Research Corp.
temperature) (1982)
Freezing point <-40T Hawley (1971)
Flash point 260°F Hawley (1971); Sax (1979)
Refractive index 1.4465-1.4515 Hawley (1971)
Vapor pressure co.01 mm (20°C) Hawley (1971)
Viscosity 323 cp (20°C) Hawley (1971)

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420 COSMETIC INGREDIENT REVIEW

USE
Cosmetic Use
United States
Ethyl Hexanediol is used as a solvent in cosmetic formulations (Nikitakis,
1988). The product formulation data submitted to the Food and Drug Adminis-
tration (FDA) in 1993 reported that Ethyl Hexanediol was used in a total of three
cosmetic product formulations (Table 2) (FDA, 1993a). Ethyl Hexanediol is also
a component of quaternium-33 (and) Ethyl Hexanediol, which has the trade name
Lanoquat 1756 (Nikitakis et al., 1991). Lanoquat 1756 was reported to be used in
five cosmetic formulations in 1993 (FDA, 19936). Concentration of use values are
no longer reported to the FDA by the cosmetic industry (Federal Register, 1992).
However, product formulation data submitted to the FDA in 1984 stated that
Ethyl Hexanediol was used at concentrations up to 5% (FDA, 1984).
Ethyl Hexanediol is used as a solvent for shampoos containing quaternium-33
and quaternium-60. These quaternaries must be sold as proprietary blends with
this solvent because the quaternization ptocess occurs in this medium (Hunting,
1983).
The FDA’s final rule for the use of Ethyl Hexanediol in shampoos to treat
dandruff is Category I11 status: The available data were insufficient to permit a
classification of this ingredient’s safety and efficacy (Federal Register, 1990).

International
In 1991 the Canadian government moved to cancel the registration of all insect
repellents containing Ethyl Hexanediol because of data suggesting that Ethyl
Hexanediol is teratogenic. The Health Protection Branch is presently investigat-
ing the use of Ethyl Hexanediol in cosmetic products [Cosmetic, Toiletry, and
Fragrance Association (CTFA), 19911.
Ethyl Hexanediol is approved for use in cosmetics in Japan (Nikko Chemicals
Co., Ltd., 1992).

Noncosmetic Use
Ethyl Hexanediol is used in medicines, as a vehicle and solvent in printing inks,
and as a chelating agent for boric acid (Hawley, 1971; Wilkinson and Moore,

TABLE 2. Cosmetic product formulation data on Ethyl Hexanediol

Total no. Total no.
formulations of formulations
Product category in category containing ingredient
Tonics, dressings, and other hair-grooming aids 494 1
Cleansing products 702 1
Other sun tan preparations 57 I
1593 totals 3

J Am Coll Toxicol, Vol. 13, No. 6, 1994

 ETHYL HEXANEDIOL 421

1982). It is used as a viscosity reducer and as a reactive diol in the manufacture of

two-package urethanes. At room temperature Ethyl Hexanediol is a conventional
solvent, but at elevated temperatures it reacts to eliminate or minimize solvent
emissions. Ethyl Hexanediol may also be used as a conditioning agent for cork
products, as a film-coalescing aid for latexes, and as an intermediate for producing
antioxidants and corrosion inhibitors (Union Carbide Corp., 1978).
In the past, Ethyl Hexanediol was used in insect repellents intended for direct
application to human skin and clothing. However, in 1991 Union Carbide Corp.
submitted data to the Environmental Protection Agency (EPA) that indicated
possible adverse developmental effects associated with Ethyl Hexanediol. After
conducting a risk assessment using these data, the EPA concluded that “the use
of [Ethyl Hexanediol] as a repellent by pregnant women represents an unaccept-
able developmental risk.’’ Registrations for all the products containing this ingre-
dient were voluntarily canceled by the companies making these products (Federal
Register, September 4, 1991; December 2, 1991).

GENERAL BIOLOGY
Absorption, Distribution, and Metabolism
Oral

In a peroral study, groups of four CDF Fischer 344 rats were administered 1.5
and 150 mgkg of [ 1,3-14C]EthylHexanediol(5-10 pCi) by gavage. Approximately
87 and 90% of the administered radioactivity were recovered from the high- and
low-dose groups, respectively. Most of the radioactivity (70-73% of the adminis-
tered dose) was found in the urine. Radioactivity was also found in the feces (7%)
and as expired 14C02(1-2%). Very little radioactivity was found in the organs and
tissues. The most measurable radioactivity was found in the kidneys, liver, and
skin. The concentration of radioactivity in the plasma had a linear dose response,
and elimination via the urine followed first-order processes. Ethyl Hexanediol
appeared to be completely metabolized in the rat and eliminated as at least two
major metabolites (Frantz et al., 1992).

Intravenous

Frantz et al. (1991) investigated the systemic disposition of Ethyl Hexanediol in

rats following intravenous injection. Groups of six male Fischer 344 rats were
slowly injected with 1.5 and 150 m a g of [I,3-l4C1EthylHexanediol(5 pCi) over
a 2-min period via the indwelling jugular cannula. Blood, urine, and feces were
collected at regular intervals, and expired I4CO2 was monitored in four animals
from each group. The rats were killed with an overdose of methoxyflurane after
48 h.
During the injection of the test material, the animals of the high-dose group
experienced temporary narcosis, which diminished within the first 5 min after
dosing. This effect was not observed in the low-dose group. The concentration of
radioactivity in the plasma samples from both groups decreased rapidly between

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422 COSMETIC INGREDIENT REVIEW

2.5 min and 24 h in a biphasic manner following first-order transfer and elimination
processes. Radioactivity concentrations in the 36- and 48-h samples could not be
quantified. The authors stated that there was a linear dose response for the 1.5- to
150-mgkg dose range of Ethyl Hexanediol.
The major route of excretion for Ethyl Hexanediol was via the urine. The
percentages of radioactivity recovered from the urine of the high- and low-dose
groups were 64.3 and 72.4%, respectively. Most of the radioactivity was excreted
within the first 12 h following administration, and elimination followed first-order
behavior similar to that characterized for total radioactivity in the plasma. Ap-
proximately 10.27% of the radioactivity was found in the feces of the high-dose
group, and 4.99% was found in samples from the low-dose group. Expired 14C02
was < 1% of the injected dose for the high-dose group, so I4CO2was not measured
for the low-dose group.
The authors also measured the concentration of unchanged Ethyl Hexanediol in
the plasma and urine samples collected from the rats. In the high-dose group,
plasma concentrations of unchanged Ethyl Hexanediol could be quantified only
up to the 18-h sample. In most cases, these concentrations closely paralleled the
curve for radioactivity, but were lower than the radioactivity levels. No unme-
tabolized Ethyl Hexanediol was found in the urine by high performance liquid
chromatography (HPLC) analysis, which indicated that Ethyl Hexanediol was
probably completely metabolized by the rats. The authors did not attempt to
identify the metabolites. However, in tests to demonstrate the existence of Ethyl
Hexanediol in conjugated form, the authors concluded that it was probably not
directly conjugated with glucuronic acid or sulfate during metabolism.
In another study, three hairless dogs were injected intravenously with 79.5 bg
of [1,3-I4C]Ethyl Hexanediol (2 FCi). The dogs were monitored in metabolism
cages for 4 days, and blood samples, urine, and feces were collected regularly.
Approximately 86% of the administered radioactivity was recovered from the
urine, most of which was eliminated within the first 24 h. Negligible amounts of
radioactivity were found in the feces. Radioactivity in the blood decreased to near
background levels 4-8 h after administration (Reifenrath et al., 1980).

Percutaneous-In Vitro

Tallant et al. (1991) compared the skin penetration of Ethyl Hexanediol in in

vitro studies using excised skin from Fischer 344 rats, New Zealand white rab-
bits, and humans (mammoplasty patients). The penetration of 150 m a g of
[ 1,3-14C]Ethyl Hexanediol was analyzed over a 6-h period using a flow-through
skin penetration chamber design. Under occlusive patches, -2-3% of the applied
dose penetrated the skin of rats, 3-5% penetrated the skin of rabbits, and 0.9%
penetrated human skin. Less radioactivity was recovered from the effluents when
tested using nonocclusive patches on human skin. This was attributed to the
evaporation of Ethyl Hexanediol from the skin.
In another study, the penetration of 0.046 and 0.3 mg/cm2 [1,3-I4C]Ethyl Hex-
anediol through excised human skin was analyzed over 1- and 12-h periods, re-
spectively. Approximately 1% of the radioactivity from the low dose penetrated

J Am CON Toxicol. Vol. 13, No. 6,1994

 ETHYL HEXANEDIOL 423

the human skin 1 h after application, and 12.0% of the radioactivity from the high
dose penetrated the skin after 12 h. Ethyl Hexanediol was fairly volatile: Approx-
imately 47.2% of the radioactivity was recovered from the vapor trap during the
12-h study and 16.2% during the 1-h study (Reifenrath and Robinson, 1982).

Percutaneous-In Vivo

Frantz et al. (1992) investigated the penetration and nonsystemic disposition of

Ethyl Hexanediol in vivo. Groups of four CDF Fischer 344 rats had 150 mgkg of
undiluted [I ,3-14C]Ethyl Hexanediol applied under occlusive patches to a 1-cm2
clipped area on their backs for 48 h. Blood samples, urine, and feces were cob
lected at regular intervals. The animals were killed with an overdose of me-
thoxyflurane 48 h after dosing, and the major organs and tissues were examined.
The average total of the applied radioactivity recovered from the rats was
107.0% for the male rats and 94.6% for the female rats. Most of the radioactivity
(55-74%) was recovered from the patch materials. The major route of excretion
was in the urine; 20-25% of the radioactivity was eliminated in a first-order man-
ner. Approximately 2-3% of the applied radioactivity was found in the feces, and
-1% was recovered as expired 14C02.Very little radioactivity was detected in the
organs and tissues. The concentration of radioactivity in the plasma peaked be-
tween 12 and 24 h and then steadily declined. While the concentration of un-
changed Ethyl Hexanediol at the high dose paralleled the radioactivity found in
the plasma, Ethyl Hexanediol represented only 1743% of the corresponding I4C
concentrations. Unchanged Ethyl Hexanediol could not be quantified for the
low-dose group. No unmetabolized Ethyl Hexanediol was found in the urine.
Using HPLC, the authors determined that Ethyl Hexanediol was excreted as at
least two major, water-soluble urinary metabolites. These metabolites were not
identified.
Percutaneous absorption was also tested using dogs. Three hairless dogs had
0.32 mg/cm2 of [1,3-I4C]Ethyl Hexanediol applied to a 5 X 5 cm2 site on their
backs. The treated area was covered with a foam pad, which had an opening
around the treated area and a nylon screen over the opening to prevent contam-
ination of the metabolism cage with radioactivity from the skin’s surface. This
device protected the treated site and allowed evaporation. A new device was
placed over the site after 24 h, and the device was removed and the site was
swabbed after 48 h. Radioactivity was measured for the two devices and the
swabbing materials, and blood samples, urine, and feces were collected regularly
for 5 days.
Approximately 62.7% of the applied radioactivity was recovered after 5 days:
513%from the foam patches, 10.3% from the urine, and 0.7% from the applica-
tion site residue. The radioactivity in the feces was at a background level, and the
radioactivity in the blood was too low to be measured (Reifenrath et al., 1980).
Similar procedures were used to study the penetration of 4 pg/cm2 of
[1,3-14C]Ethyl Hexanediol through the skin of three dogs. The results from this
study were compared with the study previously cited to determine the effect of
dose on the percentage penetration. As in the previous study, most of the radio-

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424 COSMETIC INGREDIENT REVIEW

activity was recovered from the patching materials (56.0%). Radioactivity was
also detected in the urine (7.6%) and the residue from the application site (7.1%).
The mean percentage penetration increased slightly with the greater chemical
dose (8.8 and 10.3% for the low and high dose, respectively), but this change was
not significant at the 95% confidence level (Reifenrath et al., 1981).

ANIMAL TOXICOLOGY
Acute Toxicity
Oral

Groups of five male and five female Sprague-Dawley rats were administered
undiluted Ethyl Hexanediol intragastrically. Doses of 4, 8, and 16 mVkg were
administered to the male rats and 2,4, and 8 mvkg to the female rats. The animals
were observed for signs of toxicity over a 14-day observation period. No deaths
occurred in the low-dose groups of either sex. One rat in each of the mid-dose
groups died, and all rats in the high-dose groups died. The deaths occurred be-
tween 2 h and 2 days following administration. The calculated LD50 values were
9.85 mVkg for male rats and 4.92 mVkg for female rats. Signs of toxicity during the
study included sluggishness, unsteady gait, prostration, and lacrimation. At nec-
ropsy, the rats that died had mottled lungs. No gross lesions were observed in the
animals that survived to the end of the study (Ballantyne et al., 1985).
Other reported oral LD50 values for Ethyl Hexanediol using rats were >5,OOO
mgkg (Eastman Kodak Co., 1988), 6.12 gkg (Union Carbide Corp., 1978), 2.71
gkg (Smyth et al., 1951), and 2.6 mVkg (Draize et al., 1944).

Intravenous

The intravenous LD50 values for male and female Fischer 344 rats were 131 and
176 mglkg of Ethyl Hexanediol, respectively (Frantz et al., 1991).

Dermal

Groups of five male and five female New Zealand White rabbits had undiluted
Ethyl Hexanediol applied under occlusive patches to the clipped skin of their
trunks for 24 h. The male rats received doses of 8.0, 11.3, and 16.0 mvkg, and the
females received 4.0, 8.0, and 16.0 mlkg. All of the rats from the low-dose groups
survived the 14-day observation period. Three male and two female rats from the
mid-dose groups died, and all of the males and four of the females from the
high-dose groups died. The calculated LDSovalues for male and female rats were
10.88 and 9.51 mvkg, respectively. All the deaths occurred between days 2 and 5
postadministration. Signs of toxicity included sluggishness, unsteady gait, and
prostration. The animals from both the low-dose and the mid-dose groups had
transient weight loss. At necropsy, the animals that died had mottled lungs and
some of the animals had black foci on the mucosal surface of their stomach. Two

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 ETHYL HEXANEDIOL 425

rats had a brown liquid in their pleural cavity. These lesions were not found in the
animals that survived the 14-day test period (Ballantyne et al., 1985).
Other reported dermal LD,, values of Ethyl Hexanediol for rabbits were >2O
mVkg (Eastman Kodak Co., 1988), 14.3 g/kg (Union Carbide Corp., 1978), and
10.0 mVkg (Draize et al., 1944).

Inhalation

Groups of five male and five female Wistar albino rats were exposed to atmo-
spheres saturated with a vapor of Ethyl Hexanediol for 6 h. The vapor was
generated either statically or dynamically in vapor chambers. None of the animals
died during exposure or during the 14-day observation period. The animals ex-
posed to the dynamically generated vapor were hypoactive during exposure, but
this did not occur in the animals exposed to statically generated vapor. No lesions
were observed at necropsy (Ballantyne et al., 1985).
In another study, five male and five female SpragueDawley rats were exposed
for 4 h to an aerosol of Ethyl Hexanediol. The atmospheric concentration of Ethyl
Hexanediol was 3.8 m a , and the particle size distribution had a mass median
aerodynamic diameter of 2.0 pm (with a geometric SD of 4.3 Fm). No deaths
occurred either during exposure or during the 14-day observation period. Perioral
and perinasal wetness with encrustation were observed on day 1 and were the
only signs of toxicity during the study. No gross lesions were observed in any of
the animals at necropsy (Ballantyne et al., 1985).

Short-Tern Toxicity
Oral

Groups of five male and five female rats [CD(SD)BR] were administered 0, 100,
300, and 1,OOO mg/kg/day of Ethyl Hexanediol in corn oil by gavage five times a
week for 29 days (21 total doses). A control group of rats was administered corn
oil alone. The behavior, feed consumption, and weights of the animals were
monitored throughout the study. Necropsy was performed on all of the rats, and
hematology and clinical chemistry examinations were conducted. None of the rats
died before termination of the study, and no adverse clinical signs were observed
in any of the dosage groups. The only reduction in body weight occurred in the
male rats of the 300- and 1,000-mg/kg/day treatment groups on days 21 and 28;
body weight gains were 9 and 6% lower than in the control group, respectively.
However, these differences were not statistically significant. The body weight
gain of the males from the 100-mg/kg/daytreatment group was 8% greater than in
the controls. The mean body weights of the female rats were comparable with
those of the controls in all dose groups.
AU of the treated rats had increased mean leukocyte counts regardless of ad-
ministered dose. This change appeared to be dose dependent in the female rats;
statistically significant increases were observed in the 300- and 1,000-mg/kg/day
dose groups. In male rats, the mean leukocyte count was not significantly differ-

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426 COSMETIC INGREDIENT REVIEW

ent from that of the controls. The female rats also had a statistically significant
lower platelet count in the 1,000-mg/kg/day dose group. All other hematological
parameters for both sexes were comparable with those of the controls, and no
changes in the clinical chemistry parameters were found in any of the treated rats.
Changes in organ weights occurred only in the 1,000-mglkglday treatment
group. Male rats had statistically significantly increased mean relative liver and
spleen weights. Increases were also measured in the mean absolute liver and
spleen weights, but these were not statistically significant. In female rats, the
mean absolute and relative liver weights were significantly increased. No treat-
ment-related lesions were found in any of the treated animals at necropsy or
microscopic examination of the tissues (Eastman Kodak Co., 1989~).

Dermal

Eight rabbits had 0.9 ml/kg/day of Ethyl Hexanediol applied to the clipped skin
of their abdomens five times a week for 18 weeks. Each application was rubbed
gently into the skin until it was substantially absorbed (1040 min). The rabbits
were weighed weekly and blood counts and blood chemistry were analyzed. Nec-
ropsy was performed on all of the animals at the end of the study, and the liver,
kidneys, and skin were microscopically examined. No evidence of toxicity was
observed during the study (Mellon Institute of Industrial Research, 1946).

Subchronic Oral Toxicity

Ethyl Hexanediol was administered in the feed to 10 rats for 90 days at con-
centrations ranging from 0.20 to 0.70 fig. The only sign of toxicity was reduced
growth in the rats from the high-dose group. The maximum dose that had no toxic
effects was 0.48 g/kg. No lesions were found during microscopic examination
(Smyth et al., 1951).

Dermal Initation

Ethyl Hexanediol [0.01 ml(O.009 g)] was mildly imtating to the skin of rabbits
(number unspecified) after a single application (Union Carbide Corp., 1978).
Five guinea pigs had 0.5 ml of undiluted Ethyl Hexanediol applied to the clipped
skin of their backs. A total of nine applications were made over an 1I-day period.
Slight erythema was first observed after the third application, and by the end of
the study, the animals had slight to moderate erythema. There was no evidence of
percutaneous absorption (Eastman Kodak Co., 1988).
In another study, 0.5 ml of undiluted Ethyl Hexanediol was applied under
occlusive patches for 24 h to the depilated abdomens of five guinea pigs. No signs
of irritation were observed 24 or 48 h following application or after 2 weeks
(Eastman Kodak Co., 1988).
The primary irritation potential of Ethyl Hexanediol was also investigated by
Ballantyne et al. (1985). Three male and three female New Zealand White rabbits
had 0.5 ml of undiluted Ethyl Hexanediol applied under occlusive patches to the

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 ETHYL HEXANEDIOL 427

clipped skin of their backs, and the application sites were evaluated after 1 h and
after 1 , 2 , 3 , and 7 days. Slight erythema was observed in five rabbits after the first
hour and one rabbit had well defined edema. All signs of irritation subsided by
24 h.
In the acute dermal toxicity study (described earlier in this report), signs of
inflammation, erythema, and edema were observed at the application sites of
rabbits treated with undiluted Ethyl Hexanediol (doses ranging from 4.0 to 16.0
mVkg). Erythema and edema disappeared by day 7, but desquamation was present
until the end of the study (Ballantyne et al., 1985).
A minor degree of erythema with desquamation was also present during the
short-term dermal toxicity study (described earlier in the report), in which eight
rabbits were treated with 0.9 ml/kg/day of Ethyl Hexanediol for 18 weeks (Mellon
Institute of Industrial Research, 1946).

Sensitization

Eastman Kodak Co. (1988) conducted a sensitization test following the Kodak
Footpad Method. Ten Hartley guinea pigs were inducted with 0.05 ml of 1.0%
Ethyl Hexanediol in Freund’s Complete Adjuvant and were challenged with 1.0
ml of Ethyl Hexanediol in 10.0 ml of a solution of acetone, dioxane, and guinea pig
fat. No sensitization was observed.

Ocular Irritation

The primary ocular irritation potential of Ethyl Hexanediol was investigated

using groups of New Zealand White rabbits (six rabbits per group) whose corneas
did not stain with 2% fluorescein. One group of rabbits had 0.1 ml Ethyl Hex-
anediol instilled into the inferior conjunctival sac of one eye and two other groups
of rabbits had 0.01 or 0.005 ml of Ethyl Hexanediol placed directly onto the cornea
of one eye. The eyes were examined after 1 and 24 h and after 2 , 3 , and 7-14 days,
The animals treated with 0.1 ml Ethyl Hexanediol developed mild to severe con-
junctivitis, seen as marked injection, mild to severe chemosis, and mild to marked
discharge. Moderate intis and moderate corneal injury were also observed. Only
one case of conjunctivitis resolved within 24 h. The remainder of the cases re-
solved very slowly, the eyes becoming clinically normal after 7 days. Similar
effects were observed at the lower doses (0.01 and 0.005 ml). Moderate to severe
conjunctivitis persisted for 24 h, and conjunctival injection, chemosis, and dis-
charge persisted for 2-7 days. Moderate intis and corneal injury were present for
3-7 days (Ballantyne et al., 1985).
Six New Zealand white rabbits had 0.1 ml of undiluted Ethyl Hexanediol in-
stilled into the conjunctival sac of one eye. Three of the treated eyes were im-
mediately rinsed after instillation. The eyes were observed for signs of irritation
immediately after instillation, after 1, 24, 48, and 72 h, and after 7 and 14 days.
Fluorescein staining was conducted 24 h after dosing. At the 24-h grading period,
Ethyl Hexanediol caused moderate to severe erythema and severe edema of the
conjunctivae and nictitating membranes in the unrinsed eyes. The eyelids had

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428 COSMETIC INGREDIENT REVIEW

slight erythema and edema, there was slight corneal opacity, and moderate dis-
charge was observed. Adnexal and corneal staining were also observed after
treatment with fluorescein dye. Erythema developed in the irises after 48 or 72 h.
Signs of irritation subsided by day 7 and the eyes appeared normal at day 14.
Imtation was less severe in the rinsed eyes. The conjunctivae and nictitating
membranes of the eyes had only slight to moderate erythema, and discharge
occurred only during the 1-h grading period. When the eyes were stained with
fluorescein dye, only adnexal staining occurred. The eyes of two rabbits appeared
normal after 72 h, and the eye of the third rabbit was normal by day 7 (Eastman
Kodak Co., 1988).
Carpenter and Smyth (1946) gave Ethyl Hexanediol an overall ocular irritation
grade of 5 (on a scale of 1-10, 10 being the greatest injury grade). By definition,
grade 5 means that 0.02 rnl of undiluted Ethyl Hexanediol caused an ocular im-
tation score over 5 (maximum score: 20) after a 24-h exposure period and that
0.005 ml Ethyl Hexanediol did not cause a reaction >5.

Maternal Toxicity and Teratogenicity

In a developmental toxicity probe study, groups of eight timed pregnant rats

were administered 500, 1,000, 2,000, or 4,000 mglkg Ethyl Hexanediol in corn oil
by gavage on days 6-15 of gestation. A control group of rats was administered
corn oil alone. The animals were observed throughout the study, and necropsy
was performed at the time of death or on day 20 of gestation.
Seven rats from the 4,000-mgkg group and one from the 2,000-mglkg group died
before the end of the study. These dams had signs of weakness, respiratory
difficulty, dehydration, sialorrhea, gait disturbances, nasal discharge, porphyrin
tears, diarrhea, decreased volume of feces, and unkempt haircoats. The rats from
the high-dose group also had hypothermia, partially closed eyes, and excessive
tearing. No clinical abnormalities were observed in the rats of the 500- or 1,OOO-
mgkg dose groups.
In all of the treatment groups, feed consumption was reduced during the fvst 3
days of treatment. The only statistically significant reduction occurred with the
one surviving rat from the 4,000-mgkg group. Mean body weight gains were
reduced for all the treatment groups, but the reductions were not statistically
significant. The only significant change in organ weight was a greater mean rela-
tive liver weight in the 2,000-mgkg group. The relative liver weights at the lower
doses were comparable with those of the control group.
At necropsy ,lesions were found only in the dams that died before the end of the
study. The dams from the 4,OOO-mgkg group had Ethyl Hexanediol in their stom-
achs and duodenum, necrosis of the glandular gastric mucosa, excessive mucus in
the cecum, and atrophy of the thymus and adipose tissue. The one dam from the
2,000-mgkg group that died had hemorrhage in the glandular gastric mucosa and
atrophy of the thymus and adipose tissue.
Pregnancy rates were low for the control and 1,000-mgkggroups. However, the
pregnancy rates of the other treatment groups were normal when compared with
historical controls. The numbers of resorptions and postimplantation losses were

I Am Coll Toxicol, Vol. 13. No. 6. 1994

 ETHYL HEXANEDIOL 429

significantly increased in the rats of the 2,000-mgkg group. The mean fetal body
weights from this group were significantly decreased. None of these changes were
observed in the lower-dose groups, and no changes in the mean number of corpora
lutea, implantation sites, viable fetuses per litter, or preimplantation loss were
observed in any of the treatment groups.
There was a statistically significant increase in the incidence of the following
malformations in the fetuses from the dams in the 2,OOO-mgkggroup: rudimentary
tails, missing tails, one case each of small tail and curly tail, edematous and/or
hemorrhagic tails, a tail with a cyst, curvature of the hindlimbs, arthrogryposis,
shortened trunk, umbilical hernia, and hematomas. Two fetuses from the dams of
the 1,000-mgkggroup and one fetus from the dams of the 5Wmg/kg group had
rudimentary tails, and one fetus from a dam of the 1,000-mg/kggroup had a
hematoma on the face.
The authors concluded that doses of 2,000 and 4,000 mgkg Ethyl Hexanediol
were maternally toxic and lethal and that signifcant evidence of teratogenicity
was observed only at maternally toxic doses. They noted that the number of
control fetuses was very low, which might have obscured the effects seen in the
lower-dosage groups (Eastman Kodak Co., 19896).
In another study, 1.0, 2.0, and 4.0 mlkg of undiluted Ethyl Hexanediol was
applied under occlusive patches to the skin of groups of 25 timed pregnant
SpragueDawley rats for 6 h on days 6-15 of gestation. The volume of the test
material was based upon the weight of the dam on day 6. A control group of rats
was treated with deionized water. Feed consumption and gestational body weight
were measured daily and the rats were killed on day 21 of gestation.
Signs of maternal toxicity observed in the 4.0-ml/kg/day group included skin
imtation, decreased gestational body weight gain, and increased liver weight.
Relative liver weights were also increased in dams from the 1.O- and 2.0-ml/kg/day
groups, and mild skin imtation was observed in some of the dams in the 2 . 0 - d
kg/day group. Significant changes in the other gestational parameters measured
were not observed.
There were no significant changes in the incidence of individual external or
skeletal malformations, malformations by category, or total malformations. One
visceral malformation, hydroureter, was increased in the fetuses from the dams of
the 4.0-ml/kg/day treatment group. There were also statistically significant in-
creases in the incidence of the following visceral variations in this group: fetal
atelectasis, partial fetal atelectasis, dilated lateral ventricle with no tissue depres-
sion, and bilateral dilated ureter. Additionally, a total of 13 of the 91 individual
skeletal variations were statistically increased, which the authors attributed to
reduced ossification. In the fetuses from the 2.0-mVkg/day group, the following
aberrations were observed: dilated lateral ventricle with no tissue depression,
bilateral dilated ureters, and a reduced number of caudal segments. No significant
developmental or teratogenic effects were observed in the fetuses from the 1.0-
ml/kg/day group. The authors concluded that at topical doses of 1.0, 2.0, and 4.0
ml/kg/day, Ethyl Hexanediol caused maternal effects in SpragueDawley rats,
and that at doses of 2.0 and 4.0 mlkglday, Ethyl Hexanediol appeared to be a mild
developmental toxicant (Bushy Run Research Center, 1992).

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430 COSMETIC INGREDIENT REVIEW

MUTAGENICITY

In Vitro Studies

The mutagenic potential of Ethyl Hexanediol was evaluated in the Ames test
using Salmonella ryphimurium strains TA1535, TA1537, TA1538, TA98, and
TA100. Ethyl Hexanediol was tested in triplicate at concentrations ranging from
0.3 to 28.0 mg/plate both with and without metabolic activation with rat liver S9
mix. The positive control used for all the strains of the activated protocol was
2-aminoanthracene. For the protocol without S9 activation, 4-nitro-O-
phenylenediamine was the positive control for strains TA1538 and TA98, sodium
azide was used for TA1535 and TA100, and 9-aminoacridinewas used for TA1537.
Ethyl Hexanediol was negative in both test systems for each of the strains tested
(Slesinski et al., 1988).
Ethyl Hexanediol was also tested in the quantitative assay of mutation induc-
tion at the hypoxanthine-guanine phosphoribosyl transferase locus in Chinese
hamster ovary cells (CHO/HGPRT System). CHO cells were incubated with
Ethyl Hexanediol at concentrations ranging from 1.0 to 4.5 m g / d both with and
without rat liver S9 activation. The cells were rinsed after 5 h, and cell viability
was determined after a 18-h recovery period. Periodic replating was done at 2 to
3-day intervals, and the percentage of clonable cells and the incidence of mutants
resistant to Gthioguanine were determined after 9 days. The positive controls for
the tests conducted with and without S9 activation were dimethylnitrosamine
(DMN) and ethylmethanesulfonate (EMS), respectively.
Cytotoxic effects were observed even though a 18-h recovery period was allot-
ted before evaluating colony forming ability. The mean percentage of clonable
cells from the treatment groups was not significantly different from solvent con-
trols. In tests without metabolic activation, doses of 1.0 and 4.0 mg/ml of Ethyl
Hexanediol produced statistically significant increases in the number of mutant
colonies formed. However, this was not a dose-related trend, as concentrations
between the two doses did not increase the mutation index above that of the
solvent controls. Additionally, there was a lack of agreement in duplicate cul-
tures, and the values were within the historical control range for the laboratory
(Slesinski et al., 1988).
In a sister chromatid exchange (SCE) assay, CHO cells were treated with Ethyl
Hexanediol at concentrations of 1.0-3.0 mg/ml for 2 h with S9 activation and for
5 h without S9 activation in medium with bromodeoxyuridine. After 24-28 h, the
chromosomes were harvested for SCE staining. EMS and DMN were used as
positive controls. The 3.0-mglml dose of Ethyl Hexanediol alone was cytotoxic to
the CHO cells and could not be evaluated due to a low mitotic index. However,
during the shorter exposure time when Ethyl Hexanediol was tested with S9
activation, such excessive cytotoxicity was not observed. Overall, Ethyl Hex-
anediol, both with and without metabolic activation, did not increase SCEs above
that of the negative control, and no dose-related trend relative to the concentra-
tion of Ethyl Hexanediol was found (Slesinski et al., 1988).
Ethyl Hexanediol was also tested for clastogenic activity. CHO cells were

J Am Coll Toxicol. Vol. 13, No.6, 1994

 ETHYL HEXANEDIOL 431

exposed to Ethyl Hexanediol alone for G 1 2 h or to Ethyl Hexanediol with S9

activation for 2 h. Two concentrations of S9 homogenate were used: 50 pl/5 ml
and 100 pl/5 ml. The chromosomes were harvested following exposure and chro-
mosome damage was evaluated. Triethylenemelamine (TEM) was used as the
positive control for the nonactivated test and cyclophosphamide was used in the
tests with S9 activation. In tests without metabolic activation, Ethyl Hexanediol
was tested at concentrations ranging from 1.3 to 2.0 mdml. None of these con-
centrations increased the incidence of chromosome aberrations. Under activation
conditions, 3.0-4.5 mg/ml Ethyl Hexanediol caused statistically significant in-
creases in chromosome aberrations at isolated time periods only. When activation
was induced with 50 pl S9/5 ml, positive results were reported at 8 h but not at 12
h. Similarly, when activation was induced with 100 p1 S9/5 ml, a significant in-
crease in aberrations was reported at 10 h, but at 12 h there was only a marginally
positive increase. Most of the chromosome damage was simple chromatid and
chromosome breakage. The authors stated that such damage would probably be
lethal to the cell and thus concluded that Ethyl Hexanediol did not have the
potential to cause any inheritable damage (Slesinski et al., 1988).

In Vivo Studies
Swiss-Webster mice were used to investigate the effects of Ethyl Hexanediol
upon the incidence of micronucleated polychromatic erythrocytes (mPCEs) in
peripheral blood. Groups of 5-10 mice were given intraperitoneal injections of
Ethyl Hexanediol at concentrations of 18.75, 37.5, 60,75, and 120 m a g . Blood
samples were taken after 24,48, and 72 h. A total of 2,500 PCEs were examined
for each animal. Bone marrow cytotoxicity was assessed by determining the PCE
to normochromatic (mature) erythrocyte (NCE) ratio for 1,O00 cells/animal. TEM
was used as the positive control. The two highest doses caused sedation, lethargy,
and periocular encrustation in the mice, and a few of the mice died. However, no
significant or dose-related increases in mPCEs were found in the blood from any
of the dosage groups. Also, no remarkable bone marrow cytotoxicity was evident,
as the PCE/NCE ratios of the treated animals were similar to those of controls
(Slesinski et al., 1988).
Two bone marrow cytogenetic tests were conducted using SpragueDawley
rats. In one study, groups of 10 rats were given a single intraperitoneal injection
of 60, 200, or 600 mgkg of Ethyl Hexanediol. In the other study, rats were
injected with the same concentrations of Ethyl Hexanediol daily for 5 days. The
chromosomes were sampled 12, 24, and 48 h after dosing in the acute study and
6 h after the last injection in the repeated dose study. The bone marrow was
flushed from the femurs, and the chromosomes were prepared by fixation; 100
cells/animal were evaluated. The high dose caused sedation and weight loss in the
animals treated with the high dose in both protocols, and no cumulative toxicity
was apparent as the clinical signs of toxicity were essentially the same following
both single and multiple injections. The authors noted that three animals in the
W m g k g treatment group in the repeated dose study died and were replaced by
extra high dose animals to keep the group size consistent. Ethyl Hexanediol did

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432 COSMETIC INGREDIENT REVIEW

not significantly increase chromosome damage at any time during either protocol
(Slesinski et al., 1988).
The authors also investigated the penetration of bone marrow by Ethyl Hex-
anediol. SpragueDawley rats were injected intraperitoneally with 600 m a g of
[ 1,3-14C]EthylHexanediol(10 pCi/kg) in corn oil. Two animals were killed 0.5, 1,
2, 4, and 8 h following injection, and radioactivity values in the bone and blood
were quantified. Ethyl Hexanediol was rapidly taken up by the bone marrow,
being detectable after 0.5 h and up to 8 h. The bone marrow/plasma ratios were
not significantly different between the 2- and 8-h samples, which indicated that
radioactivity uptake and elimination were at a steady state. The authors con-
cluded that Ethyl Hexanediol penetrated the bone marrow cells, and the results
supported the conclusion of the bone marrow cytogenetic test that Ethyl Hex-
anediol was not clastogenic (Slesinski et al., 1988).

CARCINOGENICITY
Groups of five New Zealand White rabbits had 0.02 ml of 10, 50, and 1 W o
Ethyl Hexanediol applied to their interior left ear twice a week for their lifetime.
A positive control group of 15 rabbits was treated with 9,10-dimethylbenz(a)an-
thracene (DMBA), and the study was terminated after 50 weeks for morphological
analysis. An untreated control group of five rabbits was allowed to die spontane-
ously. The lifespan of the animals treated with Ethyl Hexanediol was not signif-
icantly different from the survival of the untreated control rabbits. The DMBA-
treated animals developed several cutaneous ear tumors including papillomas,
keratoacanthomas, and squamous cell carcinomas. However, no cutaneous tu-
mors were found in the ears of the rabbits treated with Ethyl Hexanediol (Sten-
back, 1977).
The carcinogenic potential of Ethyl Hexanediol was also investigated using
Swiss mice. Groups of 50 female mice had 0.02 ml of 10, 50, and 100% Ethyl
Hexanediol applied to a shaved l-in2 area on their back twice a week for their
lifetime. A positive control group of mice were treated with DMBA and a negative
control group of 150 mice received no treatment. Necropsy was performed on all
of the mice. During the study, the authors noted a slight inflammation and atrophy
of the skin. The lifespan of the treated animals did not differ significantly from that
of untreated controls. However, the tumor incidence for animals treated with
Ethyl Hexanediol(46-64%) was greater than for untreated controls (42%). Tumor
incidence did not appeai to be specifically related to tumor type. The more com-
monly found neoplasms were lymphomas, lung adenomas, liver hemangiomas,
and skin tumors. These types of tumors were also found in untreated control mice.
The authors concluded that Ethyl Hexanediol did not produce a statistically sig-
nificant increase in skin tumor incidence when compared with both untreated and
positive control animals (Stenback and Shubik, 1974).
However, the EPA reviewed this study in the toxicology profile of its Pesticide
Registration Standard for Ethyl Hexanediol and found it to be inadequate. They
noted discrepancies between the number of animals tested and the number of total
tumors. Additionally, a linear trend analysis and a site-specific X*-test conducted

I Am Coll Toxicol, Vol. 13, No. 6, 1994

 ETHYL HEXANEDIOL 433

by the EPA on the data indicated a possible oncogenic potential. The EPA con-
cluded that the data were insufficient to assess the chronic effects of Ethyl Hex-
anediol (EPA, 1981).

CLINICAL ASSESSMENT OF SAFETY

Dermal Irritation
A prophetic patch test was conducted with 5% and undiluted Ethyl Hexanediol
using 106 and 30 subjects, respectively. Each subject had two applications of 0.2
ml Ethyl Hexanediol applied to the infrascapular region of the back for 48 h. One
of the sites was covered with an occlusive dressing and the other with a semi-
occlusive dressing. Evaluations of the treatment sites were made at the time of
patch removal and 24 h later. Of the 106 subjects treated with 5% Ethyl Hexane-
diol, one had barely perceptible erythema after 48 h under the semiocclusive patch
and one subject had a similar reaction at 48 and 72 h under the occlusive patch.
With undiluted Ethyl Hexanediol, similar reactions were observed in 4 of 30
subjects tested using occlusive patches and in 2 subjects using semiocclusive
patches. One case of definite erythema was observed at 72 h in a subject tested
with occlusive patches (Ballantyne et al., 1989).
Ethyl Hexanediol was also tested in a 21-day cumulative irritation study.
Twenty-seven subjects had 0.2 ml of undiluted Ethyl Hexanediol applied to two
sites on infraclavicular skin. One site was covered with an occlusive patch, and
the other with a semiocclusive patch. Applications were made daily, except for
Saturdays and Sundays, when the patch applied on Friday was left in contact for
3 days. The sites were scored at each patch removal. Under semiocclusive con-
ditions, the incidence of barely perceptible erythema increased with the number of
applications. However, only one case of definite erythema was observed after 14
applications. Similar results were observed under occlusive conditions: The cases
of marginal erythema increased with the number of applications, definite erythe-
ma developed in three subjects, and one subject had both erythema and edema
(Ballantyne et al., 1989).

Sensitization
Ballantyne et al. (1989) conducted a repeated insult patch test with 203 subjects
using undiluted Ethyl Hexanediol. Each subject had 0.2 ml of Ethyl Hexanediol
applied under an occlusive patch to the infrascapular area of the back for 24 h
three times a week for 3 weeks. After a 2-week nontreatment period, Ethyl Hex-
anediol was applied under occlusive patches for 24 h to previously untreated sites.
The challenge sites were evaluated 24 and 48 h following removal of the patch.
Two of the 202 subjects who completed the study had definite erythema following
challenge at the 48-h reading. Three subjects had questionable reactions. When
the two subjects with positive sensitization reactions were retested using occlu-
sive and semiocclusive patches, only one subject developed definite erythema and
edema when occlusive patches were used. The other subject was described as
having questionable erythema.

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434 COSMETIC INGREDIENT REVIEW

In another human repeated insult patch test, Ethyl Hexanediol was a weak
primary irritant andor weak sensitizer. Four of 200 individuals tested had a re-
action. The details of this unpublished study were not given. However, the EPA
stated in its Pesticide Registration Standard: “This study is acceptable to fulfill
the data requirement for primary dermal imtation and skin sensitization, although
it was not conducted in accordance with the requirements of the Guidelines”
(EPA, 1981).
SUMMARY
Ethyl Hexanediol is an aliphatic alcohol that is used as a solvent in cosmetic
formulations. Oral and intravenous studies indicate that it is completely metabo-
lized in the rat and rapidly eliminated in the urine as at least two major rnetabo-
lites. Ethyl Hexanediol is also absorbed through the skin of rats and dogs.
Ethyl Hexanediol was slightly toxic to rats in acute oral studies. Reported LD50
values for rats were 4.92 mykg (females), 9.85 mvkg (males), >5,000 mgkg, 6.12
g/kg, 2.71 g/kg, and 2.6 mlkg. Dermal LD50 values for rabbits were 9.51 mYkg
(females), 10.88 mVkg (males), >20 ml/kg, 14.3 g/kg, and 10.0 mVkg. Ethyl Hex-
anediol was not toxic in inhalation studies with rats.
Ethyl Hexanediol was slightly toxic in subchronic oral studies. The most sig-
nificant effects were reduced growth and increased hepatic weights. It also caused
mild to moderate irritation when applied to the skin of guinea pigs and rabbits.
However, no evidence of sensitization was found. Ethyl Hexanediol was a mod-
erate to severe ocular irritant in rabbits.
In a developmental toxicity study, 2,000- and 4,000-mg/kg doses of Ethyl Hex-
anediol given orally were maternally toxic and lethal, and significant evidence of
teratogenicity was observed at maternally toxic doses only. In a dermal develop-
mental toxicity study, 1.0, 2.0, and 4.0 ml/kg/day Ethyl Hexanediol caused ma-
ternal effects, and at doses of 2.0 and 4.0 ml/kg/day it appeared to be a mild
developmental toxicant.
There was no evidence that Ethyl Hexanediol was mutagenic or had DNA
damage potential when tested with the Ames test, the CHO/HGPRT gene muta-
tion test system, and the SCE test both with and without metabolic activation.
Ethyl Hexanediol was also negative in the in vivo micronucleus test and bone
marrow cytogenetic tests. The only evidence of clastogenicity was reported in two
in vitro chromosome damage tests with CHO cells. These effects were observed
in the presence of S9 activation only and were observed for a brief time span only.
In dermal carcinogenicity studies, no dose-related increases in tumor incidence
were observed.
In clinical studies, Ethyl Hexanediol was a weak primary irritant, weak cumu-
lative irritant, and weak sensitizer.
DISCUSSION
The Cosmetic .Ingredient Review (CIR) Expert Panel noted the lack of imtation
when Ethyl Hexanediol was tested in humans at a concentration of 5%. This
contrasts with animal dermal irritation data, suggesting that positive findings of
irritation in animals exposed to undiluted Ethyl Hexanediol have limited rele-

J Am Coll Toxicol, Vol. 13, No. 6. 1994

 ETHYL HEXANEDIOL 435

vance. Based on the available data on use, the Panel believes that 5% is also the
highest concentration at which the ingredient is actually used.
The Panel noted the absence of data on the absorbance of Ethyl Hexanediol in
the ultraviolet region. However, based on the chemical structure of this ingredi-
ent, it was agreed that it was not likely that there would be signifcant absorption
in the UVA or UVB regions. While there was likewise no information on possible
impurities in Ethyl Hexanediol, the Panel considered it unlikely that toxic impu-
rities would be present and concluded that the lack of such data did not preclude
making a safety assessment of this ingredient.
The Panel did express concern about the evidence of weak teratogenicity in rats
following dermal exposure to undiluted Ethyl Hexanediol. It was believed, how-
ever, that no such effect would occur in humans; the high levels shown to be
weakly teratogenic in animals extrapolate to kilogram quantities of cosmetic for-
mulation in a human exposure. Such a use pattern was considered unlikely.
CONCLUSION
On the basis of the animal, clinical, and use data presented in this report, the CIR
Expert Panel concludes that Ethyl Hexanediol is safe as a cosmetic ingredient.
Acknowledgment: Susan N. J. Pang, Scientific Analyst and Writer, prepared this report.
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