Article

International Journal of Toxicology

31(Supplement 3) 269S-295S
Safety Assessment of Isoparaffins as ª The Author(s) 2012
Reprints and permission:
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Used in Cosmetics DOI: 10.1177/1091581812463087
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Wilbur Johnson Jr1, Wilma F. Bergfeld2, Donald V. Belsito2,

Ronald A. Hill2, Curtis D. Klaassen2, Daniel Liebler2,
James G. Marks Jr2, Ronald C. Shank2, Thomas J. Slaga2,
Paul W. Snyder2, and F. Alan Andersen3

Abstract
The safety of isoparaffins as used in cosmetic products is reviewed in this safety assessment. These ingredients function mostly as
solvents and also function as emollients in the 0001% to 90% concentration range. The Cosmetic Ingredient Review (CIR) Expert
Panel has reviewed relevant animal and clinical data and concluded that these ingredients are safe in the present practices of use
and concentration described in this safety assessment.

Keyword
isoparaffins

Introduction Related Cosmetic Ingredient Review (CIR) final safety

assessments on fossil and synthetic waxes, including paraffin1
Isoparaffinic hydrocarbons (isoparaffins) are branched alkanes
and 2 other branched alkanes, isobutane and isopentane,2 have
that function mostly as solvents in cosmetics. The safety of the
been published. The CIR Expert Panel concluded that fossil
following isoparaffins is reviewed:
and synthetic waxes, including paraffin, and isobutene and
isopentane are safe in the present practices of use and concen-
 C7-8 isoparaffin; tration. These 2 conclusions were confirmed in 2005.3,4
 C8-9 isoparaffin;
 C9-11 isoparaffin;
 C9-12 isoparaffin;
Chemistry
 C9-13 isoparaffin;
 C9-14 isoparaffin; Definition and Structure
 C9-16 isoparaffin;
The systematic name for the paraffins is alkanes (CnH2nþ2);
 C10-11 isoparaffin;
isoparaffins are branched alkanes. Definitions, other chemical
 C10-12 isoparaffin;
names, and cosmetic ingredient functions for the isoparaffins
 C10-13 isoparaffin;
reviewed in this safety assessment are included in Table 1. The
 C11-12 isoparaffin;
naming convention for many of these ingredients, for example,
 C11-13 isoparaffin;
C7-8 isoparaffin, connotes that the ingredient is a mixture of
 C11-14 isoparaffin;
branched chain aliphatic hydrocarbons with 7 or 8 carbons in
 C12-14 isoparaffin;
the alkyl chain. In the case of C18-70 isoparaffin, the mixture
 C12-20 isoparaffin;
has a broad range of chain lengths.
 C13-14 isoparaffin;
 C13-16 isoparaffin;
 C18-70 isoparaffin; 1
Cosmetic Ingredient Review Senior Scientific Analyst/Writer
 C20-40 isoparaffin; 2
Cosmetic Ingredient Review Expert Panel Member
3
 C15-35 isoparaffin/isoalkylcycloalkanes; Director, Cosmetic Ingredient Review
 Isooctane;
Corresponding Author:
 Isohexadecane; F. Alan Andersen, Cosmetic Ingredient Review, 1101 17th Street, NW, Suite
 Isododecane; 412, Washington, DC 20036, USA.
 Isoeicosane. Email: [email protected]
270S International Journal of Toxicology 31(Supplement 3)

Table 1. Isoparaffinic Hydrocarbons.20

Chemical names/CAS nos. Trade names Definitions Functions in cosmetics

C7-8 isoparaffin; alkanes, C7-8-iso-; CAS Isopar C and Soltrol 10 Mixture of branched chain Solvents; viscosity decreasing
No. 70024-92-9 Isoparaffin Solvent aliphatic hydrocarbons with 7 agents
or 8 carbons in the alkyl chain.
C8-9 isoparaffin; alkanes, C8-9-iso-; CAS Isopar E Mixture of branched chain Solvents; viscosity decreasing
No. 246538-71-6 aliphatic hydrocarbons with 8 agents
or 9 carbons in the alkyl chain.
C9-11 isoparaffin; alkanes, C9-11-iso-; CAS Soltrol 100 Isoparaffin Mixture of branched chain Solvents; viscosity decreasing
No. 68551-16-6 Solvent aliphatic hydrocarbons with 9 agents
to 11 carbons in the alkyl
chain.
C9-12 isoparaffina Isane IP 155 Mixture of branched chain Solvents; viscosity decreasing
aliphatic hydrocarbons with 9 agents
to 12 carbons in the alkyl
chain.
C9-13 isoparaffin; alkanes, C9-13-iso-; CAS Shellsol T Mixture of branched chain Solvents; viscosity decreasing
No. 246538-72-7 aliphatic hydrocarbons with 9 agents
to 13 carbons in the alkyl
chain.
C9-14 isoparaffin; alkanes, C9-14-iso-; CAS Mixture of branched chain Solvents; viscosity decreasing
No. 246538-73-8 aliphatic hydrocarbons with 9 agents
to 14 carbons in the alkyl
chain.
C9-16 isoparaffin Mixture of branched chain skin-conditioning agent-
aliphatic hydrocarbons with 9 emollient; solvents
to 16 carbons in the alkyl
chain.
C10-11 isoparaffin; alkanes, C10-11-iso-; Isopar G Mixture of branched chain Solvents; viscosity decreasing
CAS No. 246538-75-0 aliphatic hydrocarbons with 9 agents
to 16 carbons in the alkyl
chain.
C10-12 isoparaffin Mixture of branched chain Solvents; viscosity decreasing
aliphatic hydrocarbons with 10 agents
to 12 carbons in the alkyl
chain.
C10-13 isoparaffin; alkanes, C10-13-iso-; Isane IP 175 and Mixture of branched chain Solvents
CAS No. 68551-17-7 Shellsol TD aliphatic hydrocarbons with 10
to 13 carbons in the alkyl
chain.
C11-12 isoparaffin; alkanes, C11-12-iso-; Isopar H and Isopar K Mixture of branched chain Skin-conditioning agents—mis-
CAS No. 246538-76-1 aliphatic hydrocarbons with 11 cellaneous; solvents
to 12 carbons in the alkyl
chain.
C11-13 isoparaffin; alkanes, C11-13-iso-; Isopar L Mixture of branched chain Solvents
CAS No. 246538-78-3 aliphatic hydrocarbons with 11
to 13 carbons in the alkyl
chain.
C11-14 isoparaffin Isane IP 185 Mixture of branched chain Solvents; viscosity decreasing
aliphatic hydrocarbons with 11 agents
to 14 carbons in the alkyl
chain.
C12-14 isoparaffin; alkanes, C12-14-iso-; Soltrol 170 Isoparaffin Mixture of branched chain Solvents
CAS No. 68551-19-9 Solvent aliphatic hydrocarbons with 12
to 14 carbons in the alkyl
chain.
C12-20 isoparaffin Isopar V Solvent Mixture of branched chain Skin-conditioning agents—emol-
aliphatic hydrocarbons with 12 lient; solvents
to 20 carbons in the alkyl
chain.
(continued)
Jr et al 271S

Table 1. (continued)

Chemical names/CAS nos. Trade names Definitions Functions in cosmetics

C13-14 isoparaffin; alkanes, C13-14-iso-; Isopar N Fluid and Mixture of branched chain Solvents
CAS No. 246538-80-9 Isopar M aliphatic hydrocarbons with 13
to 14 carbons in the alkyl
chain.
C13-16 isoparaffin; alkanes, C13-16-iso-; Isopar P and Soltrol Mixture of branched chain Solvents
CAS No. 68551-20-2 220 Isoparaffin aliphatic hydrocarbons with 13
Solvent to 16 carbons in the alkyl
chain.
C18-70 isoparaffin; alkanes, C18-70-iso-; PME Mixture of branched chain Skin-conditioning agents—
CAS No. 246538-80-9 aliphatic hydrocarbons with 18 occlusive
to 70 carbons in the alkyl
chain.
C20-40 isoparaffin; alkanes, C20-40-iso-; Mixture of branched chain Skin-conditioning agents—emol-
CAS No. 246538-81-8 aliphatic hydrocarbons with 20 lient; solvents
to 40 carbons in the alkyl
chain.
C15-35 isoparaffin/isoalkylcycloalkanes A petroleum fraction consisting Skin-conditioning agents—
chiefly of C15-35 branched miscellaneous
chain hydrocarbons and
branched chain cyclic
hydrocarbons.
Isododecane; 1,1-dineopentylethylene; Branched chain aliphatic Fragrance ingredients; solvents
heptane, 2,2,6,6-tetramethyl-4- hydrocarbon with 12 carbons.
methylene-; 2,2,4,6,6- The formula for this isoparaffin
pentamethylheptane; and 2,2,6,6- is included in Figure 1.
tetramethyl-4-methyleneheptane; CAS
Nos. 141-70-8, 13475-82-6, 31807-55-3,
and 93685-81-5
Isoeicosane; CAS Nos. 52845-07-5 and Branched chain aliphatic Skin-conditioning agents—emol-
93685-79-1 hydrocarbon with 20 carbons lient; solvents
in the alkyl chain. The formula
for this isoparaffin is included
in Figure 1.
Isohexadecane; 2,2,4,4,6,6,8 Branched chain aliphatic Skin-conditioning agents—emol-
heptamethylnonane and nonane, hydrocarbon with 16 carbons. lient; solvents
2,2,4,4,6,8,8-heptamethyl-; CAS No. The formula for this isoparaffin
4390-04-9, 60908-77-2, and 93685-80-4 is included in Figure 1.
Isooctane; isobutyltrimethylmethane and Hydrocarbon that conforms to Solvents
2,2,4-trimethylpentane; CAS No. 540- the formula in Figure 1.
84-1 and 26635-64-3
a
The International Cosmetic Ingredient Dictionary and Handbook monograph on C9-12 isoparaffin does not include the systematic name (ie, alkanes, C9-12-iso-).
Isane IP155 is the only tradename for C9-12 isoparaffin that is included in the dictionary. However, according to another source,13 Isopar G and Isopar H are
synonyms for alkanes, C9-12-iso-, and both tradename materials are sold under the CAS number 90622-57-4.

Chemical and Physical Properties Stability/Reactivity

Isooctane (colorless liquid) is practically insoluble in water, Branched aliphatic hydrocarbons are predominantly C10-15
somewhat soluble in absolute alcohol, and soluble in the fol- isoparaffinic hydrocarbons. These chemicals are quite stable
lowing chemicals: benzene, toluene, xylene, chloroform, ether, and relatively unreactive, such that polymerization will not
carbon disulfide, and carbon tetrachloride.5 Additional proper- occur. However, they are incompatible with strong oxidants
ties of isoparaffins are included in Tables 2 and 3. (eg, liquid chlorine, sodium hypochlorite, or concentrated
Properties of isoparaffinic hydrocarbon tradename materials O2). The incomplete combustion of these compounds may pro-
produced by various companies are included in Tables 4 and 5. duce CO and aldehydes.6
Branched aliphatic hydrocarbons that are predominantly Isooctane, an example of this class of compounds, is con-
C10-15 isoparaffinic hydrocarbons in Table 4 are colorless to sidered stable under normal ambient and anticipated storage
water-white liquids with a faint petroleum odor.6 Isopar C is and handling conditions of temperature and pressure. It may
one of the tradename materials included in Table 5. According react with oxygen and strong oxidizing agents, such as chlo-
to Exxon Company, Isopar C is approximately 85% isooctane.7 rates, nitrates, peroxides, and so on. Hazardous decomposition
272S International Journal of Toxicology 31(Supplement 3)

products include simple hydrocarbons and carbon oxides. virtually no aromatics or sulfur compounds.10 The INEOS sales
Hazardous polymerization is not expected to occur.8 specification for isododecane is as follows11:

 Sum of C12 hydrocarbons (% by weight): 98 min.

Methods of Production  Sum of C8 and C16 hydrocarbons (% by weight): 2 max.
 Aromatics (mg/kg): 1 max.
Alkylation is the chemical combination of 2 light hydrocarbon  Carbonyls (mg/kg): 5 max.
molecules to form a heavier one and involves the reaction of  Bromine index (mgBr2/100 g): 15 max.
butenes in the presence of a strong acid catalyst, such as sul-  Sulfur (mg/kg): 1 max.
furic or hydrofluoric acid. The product is a heavier multi-  Peroxides (mg/kg, calculated as H2O2): 1 max.
branched isoparaffin. Propene and various pentenes may be  Water (mg/kg): 50 max.
used to produce C7 or C9 isoparaffins. Additionally, isomeriza-  Evaporation residue (mg/100 mL): 1 max.
tion is a catalytic process that converts normal paraffins to  Neutralization number (mg KOH/g): 0.01 max.
isoparaffins. The feed is usually light virgin naphtha and, the
catalyst, platinum on an alumina or zeolite base.9 According to Reportedly, according to the hydrocarbon solvent producers,
Ineos, their manufacturing process does not start with naptha; a the actual composition of Isopar G and Isopar H (tradenames
pure C4 stream rich in isobutylene is used, leading to C8, C12, for C10-11 isoparaffin and C11-12 isoparaffin, respectively)
C16, and C20 isoparaffins.10 may be different from batch to batch within a specific producer
According to Ineos oligomers, their manufacturing process and may vary from producer to producer, depending upon the
of isoparaffins does not start with naptha. A pre C4 steam rich actual feedstock used to prepare the product. Data on average
in isobutylene is used, leading to C 8, C 12 , C 16 , and C20 composition indicate that Isopar G contains mostly C 10
isoparaffins. (53% w/w) and that Isopar H contains mostly C 12
The production of isododecane has been described as a (60% w/w). The average Isopar H branching is 3.25 (average
patented process from a prepurified isobutene (branched C4) number of branches/molecule), and estimates for the number of
containing feedstock and, therefore, is totally sunthetic. The different branches are as follows: C (0.6), CH (2), CH2 (4.2),
dimethyl branches (termed as germinal or gem dimethyls) in and CH3 (5.3). Additionally, the producers have provided
the isobutene monomer are retained in the final product.11 information indicating that 5% to 15% w/w of the substance
2,2,4-Trimethylpentane (isooctane) is synthesized from the consists of cyclic alkanes, typically C6 with varying degrees of
catalytic hydrogenation of trimethylpentene with a nickel branching.13
catalyst.12 Both Exxon and Texaco have reported benzene (<0.1 ppm) as
an impurity for all of their isoparaffinic products, and data from
Ricoh Corporation in Japan established that benzene contamina-
Composition/Impurities tion was <0.2 ppm for Isopar G. These include, but do not appear
to be limited to C9 to C15 chain lengths.6 According to another
According to Ineos oligomers, isoparaffin substances are pro-
publication, C9-C13 aliphatic solvents ( 2% aromatics) contain
duced from well-defined feedstocks and are very pure.10
<1 ppm benzene.14
Isododecane (a.k.a. hydrocarbons, C4, 1,3-butadiene-free,
As direct food additives, isoparaffinic petroleum hydrocar-
polymd., triisobutylene fraction, hydrogenated [CAS No.
bons synthesized from petroleum gases consist of a mixture of
93685-81-5]) is a mixture of highly branched C12 isoparaffins,
liquid hydrocarbons that meet the following specifications (21
mainly the 2,2,4,6,6-pentamethylheptane isomer (typically
CFR 172.882).15
*85%).10 The structure of this isomer is close to a fully per-
methylated hydrocarbon structure, containing the maximum  Boiling point: 93 C to 260 C
number of methyl groups. Isododecane also contains *15%  Ultraviolet (UV) absorbance at 260 to 319 nm: 1.5 max.
of other pentamethylheptanes that have properties that are sim-  UV absorbance at 320 to 329 nm: 0.08 max.
ilar to the main isomer.11  UV absorbance at 330 to 350 nm: 0.05 max.
Isoeicosane (hydrocarbons, C4, 1,3-butadiene-free, polymd.,  Nonvolatile residual: 0.002 g/100 mL max.
pentaisobutylene fraction, hydrogenated [CAS No. 93685-79-
1]) is a mixture of highly branched C20 isoparaffins, with not Additionally, these direct food additives may contain antioxi-
more than 2% of C16 isoparaffins. Isohexadecane (hydrocar- dants authorized for use in food, in an amount not to exceed
bons, C4, 1,3-butadiene-free, polymd., tetraisobutylene frac- that reasonably required to accomplish the intended technical
tion, hydrogenated [CAS No. 93685-80-4]; minimum purity effect nor to exceed any prescribed limitations.15 The boiling
of 99%) is a mixture of highly branched C16 isoparaffins with point specification for isoparaffinic petroleum hydrocarbons as
trace amounts of C12 and C20 paraffins of similar structure. indirect food additives is 63 C to 260 C (21 CFR 178.3530),16
Isooctane (90% 2,2,4-trimethylpentane [CAS No. 540-84-1] and the preceding specifications relating to direct food additive
is a mixture of C8 isoparaffins.10 use also apply.
Isododecane is virtually free of aromatics, sulfur-containing Petroleum hydrocarbons classified as odorless and light
molecules, and polar compounds and isooctane also contains (a mixture) is also an approved direct food additive. It is a
Jr et al 273S

Table 2. Properties of Isoparaffins.101

Specific gravity
Chemical Molecular weight Log P (SG)/density (D), g/cm3 Vapor pressure Boiling point Flash point

Isododecane 168.32 5.813 + 0.254 0.7599 7.35E01 Torr 177.7 to 178.0 C 56.7 + 8.1 C
Isohexadecane 226.44 7.976 + 0.238 0.772 + 0.06 6.02E02 Torr 240 C 95.6 C
Isooctane 114.23 4.373 + 0.206 1.126 4.52Eþ01 Torr 99.6 to 99.7 C 7.8 C

Table 3. Additional Properties of Isododecane.11

Cosmetic Registration Program (VCRP) in 2010, the following
Property Value ingredients were being used in cosmetics. C7-8 isoparaffin,
C8-9 isoparaffin, C9-11 isoparaffin, C10-11 isoparaffin,
Density 0.75 g/ml at 20 C
C11-12 isoparaffin, C11-13 isoparaffin, C12-14 isoparaffin,
Refractive index 1.421 to 1.422 at 20 C
Dielectric constant 2.12 at 20 C C13-14 isoparaffin, C13-16 isoparaffin, C18-70 isoparaffin,
Surface tension 22.6 mN/m at 20 C isododecane, isoeicosane, and isohexadecane.21 These data are
Relative vapor density 5.9 (air ¼ 1) summarized in Table 6. Isooctane is not included in the VCRP
Boiling range 176 C to 192 C database; however, Isopar C (C7-8 Isoparaffin) contains
Autoignition temperature 410 C approximately 85% isooctane. Independent of these data, the
Freezing point 81 C results of a survey of ingredient use concentrations that was
conducted by the Personal Care Products Council in 2010, also
shown in Table 6, indicate that the following ingredients were
mixture of liquid hydrocarbons derived from petroleum or
being used: C8-9 isoparaffin (5%-40%), C9-11 isoparaffin
synthesized from petroleum gases and is chiefly paraffinic,
(1%-18%), C10-13 isoparaffin (0.08%-0.60%), C11-12 isopar-
isoparaffinic, or naphthenic in nature. This food additive meets
affin (1%-67%), C11-13 isoparaffin (1%-27%), C13-14 isopar-
the following specifications (21 CFR 172.884)17:
affin 0.0001%-75%), C13-16 isoparaffin (0.40%-18%),
 Odor is faint and not kerosenic isododecane (0.008%-90%), isoeicosane (0.3%-37%), and iso-
 Initial boiling point is 300 F min. hexadecane (0.2%-42%).22
 Final boiling point is 650 F max. No uses of the following isoparaffins were reported in the
 UV absorbance at 280 to 289 nm: 4.0 max. 2010 VCRP database or in the Personal Care Products Council
 UV absorbance at 290 to 299 nm: 3.3 max. survey conducted in 2010: C9-12 isoparaffin, C9-13 isoparaf-
 UV absorbance at 300 to 329 nm: 2.3 max. fin, C9-14 isoparaffin, C9-16 isoparaffin, C10-12 isoparaffin,
 UV absorbance at 330 to 360 nm: 0.8 max. C11-14 isoparaffin, C12-20 isoparaffin, C20-40 isoparaffin,
and C15-35 isoparaffin/isoalkylcycloalkanes. The results of a
The preceding specifications for odorless light petroleum subsequent 2010 use concentration survey by the Personal Care
hydrocarbons as a direct food additive is also applicable to its Products Council confirmed that C15-35 isoparaffin/isoalkyl-
use as an indirect food additive (21 CFR 178.3650).18 cycloalkanes is not being used in cosmetic products.23
Cosmetics containing the ingredients reported as being used
Analytical Methods may be applied to the skin, nails, or hair, or, incidentally, may
come in contact with eyes and mucous membranes. Products
Gas chromatography has been used to identify isoparaffins.19 containing these ingredients may be applied as frequently as
Specifically, isooctane has been identified using gas chromato- several times per day and may come in contact with the skin,
graphy with simultaneous flame ionization detection and nails, or hair for variable periods following application. Daily
radiolabeling analytical techniques.7 or occasional use may extend over many years.
C11-13 isoparaffin, C13-14 isoparaffin, and isododecane
Use are used in hair sprays, and effects on the lungs that may be
induced by aerosolized products containing these ingredients
Purpose in Cosmetics are of concern.
Most of the isoparaffins reviewed in this safety assessment The aerosol properties that determine deposition in the
function as solvents in cosmetics, and these ingredients are also respiratory system are particle size and density. The parameter
used as emollients.20 Additional functions are included in most closely associated with deposition is the aerodynamic
Table 1. diameter, da, defined as the diameter of a sphere of unit density
possessing the same terminal settling velocity as the particle in
question. In humans, particles with an aerodynamic diameter of
Scope and Extent of Use in Cosmetics 10 mm are respirable. Particles with a da from 0.1 to 10 mm
According to information supplied to the Food and Drug settle in the upper respiratory tract and particles with a da < 0.1
Administration (FDA) by industry as part of the Voluntary mm settle in the lower respiratory tract.24,25
274S International Journal of Toxicology 31(Supplement 3)

Table 4. Properties of Isoparaffinic Tradename Materials.6

Predominant Average molecular Boiling range, Specific gravity, Flash point,

Producer Material carbon length CAS No. weight EC g/mL EC

Exxon Isopar G C10-11 64742489 149 155 to 176 0.748 40

Isopar H C11-12 64742489 160 169 to 193 0.759 49
Isopar K C11-14 64742489 164 174 to 197 0.761 49
Isopa L C11-13 64742489 171 185 to 206 0.767 60
Isopar M C12-15 64742478 191 205 to 254 0.783 71
Phillips Soltrol 50 C8-10 68551155 116 118 to 148 0.72 10
Petroleum Soltrol 100 C9-11 68551166 142 157 to 173 0.74 41
Soltrol 130 C10-13 68551177 158 176 to 208 0.75 56
Soltrol 145 C5-16 68551188 157 171 to 299 0.77 53
Soltrol 170 C10-14 68551199 185 218 to 238 0.778 85
Soltrol 220 C13-17 64741737 206 232 to 288 0.809 106
Shell Shell Sol 71 C9-12 64741657 158 179 to 202 0.76 52
Texaco Texsolve S-2 C9-10 64742887 135 156 to 157 0.778 39
Texsolve S C8-11 64742887 141 157 to 196 0.783 40.5
Texsolve S-66 C8-11 64742887 142 160 to 187 0.778 40.5
Texsolve S/LO C8-11 64742887 143 161 to 190 0.7781 40.5

Table 5. Properties of Isopar Isoparaffinic Hydrocarbon Solvents.102 Synthetic isoparaffinic petroleum hydrocarbons are used as
Predominant Vapor pressure direct and indirect food additives. Specifications for these
Materiala carbon length Specific gravity (at 38 C) classes of direct and indirect food additives are included in the
earlier section on Composition/Impurities (21 CFR 172.882;
Isopar C C7-8 0.7 13.1 Torr 178.3530).15,16
Isopar E C8-9 0.72 6.9 Torr Odorless light petroleum hydrocarbons, a mixture that is
Isopar G C10-11 0.75 1.9 Torr
chiefly paraffinic, isoparaffinic, or naphthenic in nature, is used
Isopar H C11-12 0.76 0.8 Torr
as a direct and indirect food additive. Specifications for these
a
All manufactured by Exxon Corporation. classes of direct and indirect food additive mixture are included
in the earlier section on Composition/Impurities (21 CFR
Particle diameters of 60 to 80 mm and 80 mm have been 172.884; 178.3650).17,18
reported for anhydrous hair sprays and pump hairsprays, According to Ineos, isododecane is used in the polymeriza-
respectively.26 In practice, aerosols should have at least 99% tion process, where it is used as either a solvent or a dispersing
of their particle diameters in the 10 to 110 mm range and the agent for high-reactivity organic peroxide catalysts.10 High-
mean particle diameter in a typical aerosol spray has been activity peroxide catalysts used in the production of polyvinyl
reported as *38 mm.27 Therefore, most aerosol particles are chloride and in cross-linked unsaturated polyester are fre-
deposited in the nasopharyngeal region and are not respirable. quently dissolved in isododecane.11 Isoeicosane has been used
as a heat transfer medium for heating and cooling circuits used
in chemical processes, particularly in conjunction with isohex-
Noncosmetic Use adecane. Other applications of isoeicosane include hydraulic
Isopar E is a mixture of predominantly C8-C9 isoparaffinic fluids and as an extender in silicone-based dental impression
hydrocarbons that has been used as a solvent in industrial and materials.10
consumer products, including, but not limited to, typewriter
correction fluids.28
Liquid gasoline is a complex mixture of petroleum chemi- Toxicokinetics
cals. In addition to other components, this complex mixture
consists of approximately 60% to 75% alkanes (paraffins) that
Isooctane—Inhalation Exposure
comprise straight-chain hydrocarbons (C4-C12) and isoparaf- Groups of 15 male F344 rats were exposed for 2 hours,
fins (branched-chain hydrocarbons) with approximately the nose-only, to 14C-labeled isooctane vapor at concentrations
same range of chain lengths.29 2,2,4-Trimethylpentane (isooc- of *1 and 350 ppm. Absorbed 14C-isooctane equivalents
tane) is used primarily in the alkylation step to derive high- were eliminated almost exclusively via the kidneys, and
octane gasoline fuels. 12 California phase-2 reformulated excretion was protracted over the entire 70 hours postexpo-
gasoline contains isooctane at a concentration of 32.1%.30 sure observation period. Of all, 1% to 2% of the
14
According to the US Pharmacopoeia, use of ACS reagent C-isooctane equivalents inhaled at either exposure concen-
grade isooctane is the reagent specification for prescription and tration (*1 or 350 ppm) remained in the carcass 70 hours
over-the-counter drug products.31 after inhalation exposure.32
 Table 6. Current Frequency and Concentration of Use According to Duration and Type of Exposure Provided in 2010.a
C7-8 isoparaffin C8-9 isoparaffin C9-11 isoparaffin C10-11 isoparaffin C10-13 isoparaffin
# of uses Conc. (%) # of uses Conc. (%) # of uses Conc. (%) # of uses Conc. (%) # of uses Conc. (%)
Exposure type
Eye area NR NR 18 5 to 11 8 1 to 18 1 NR NR NR
Possible ingestion NR NR NR NR NR NR NR NR NR NR
Inhalation NR NR NR NR NR NR NR NR NR NR
Dermal contact NR NR NR NR 2 2 2 NR NR NR
Deodorant (underarm) NR NR NR NR NR NR NR NR NR NR
Hair—noncoloring NR NR NR NR NR NR 1 NR NR NR
Hair—coloring NR NR NR NR NR NR NR NR NR NR
Nail 1 NR NR 40 NR NR NR NR NR NR
Mucous membrane NR NR NR NR NR NR NR NR NR NR
Bath products NR NR NR NR 2 2 NR NR NR NR
Baby products NR NR NR NR NR NR NR NR NR NR
Duration of use
Leave-on 1 NR 18 5 to 40 8 1 to 18 2 NR NR 0.08 to 0.60
Rinse off NR NR NR NR 2 2 2 NR NR NR
Totals/conc. range 1 NR 18 5 to 40 10 1 to 18 4 NR NR 0.08 to 0.60
C11-12 isoparaffin C11-13 isoparaffin C12-14 isoparaffin C13-14 isoparaffin C13-16 isoparaffin
Exposure type
Eye area 90 9 to 67 5 0.3 2 NR 68 0.005 to 6 4 NR
Possible ingestion 1 12 to 25 NR NR NR NR NR 0.2 to 1 NR NR
Inhalation NR 2 3 NR NR NR 5 52 NR NR
Dermal contact 90 16 to 35 23 2 9 NR 754 0.001 to 9 16 0.4 to 2
Deodorant (underarm) NR NR NR NR NR NR 1 NR NR NR
Hair—noncoloring NR 1 to 2 5 1 1 NR 92 0.2 to 75 9 18
Hair—coloring NR NR NR NR NR NR NR 0.5 to 13 NR NR
Nail NR 35 1 27 NR NR 2 0.02 to 0.9 1 NR
Mucous membrane NR NR NR NR NR NR 3 0.06 to 0.6 NR NR
Bath products NR NR NR NR NR NR 1 NR NR NR
Baby Products NR NR NR NR NR NR 5 NR NR NR
Duration of use
Leave-on 119 9 to 67 34 0.3 to 27 10 NR 818 0.001 to 65 24 0.4 to 18
Rinse off 2 20 1 NR NR NR 29 0.2 to 75 2 NR
Totals/conc. range 121 1 to 67 35 0.3 to 27 10 NR 847 0.001 to 75 26 0.4 to 18
C18-70 isoparaffin Isododecane Isoeicosane Isohexadecane
Exposure type
Eye area NR NR 205 3 to 67 10 2 to 9 87 0.8 to 41
Possible ingestion NR NR 58 3 to 84 15 11 to 37 5 4 to 30
Inhalation NR NR 13 4 to 33 NR 8 NR 3 to 18
Dermal contact 1 NR 387 0.008 to 62 66 0.5 to 5 541 0.2 to 42
Deodorant (underarm) NR NR NR 0.5 NR NR NR NR
Hair—noncoloring NR NR 41 0.06 to 83 1 0.3 to 16 47 0.3 to 22
Hair—oloring NR NR 1 2 NR NR NR NR
Nail NR NR NR 28 to 90 NR NR 1 0.6
Mucous membrane NR NR NR 0.8 NR 4 NR 0.7 to 6
Bath products NR NR NR 6 NR NR NR 0.2 to 3
Baby products NR NR NR NR NR NR 1 NR
Duration of use
Leave-on 1 NR 482 0.008 to 90 68 0.3 to 37 531 0.2 to 42
Rinse off NR NR 36 0.06 to 83 1 5 65 0.2 to 41
Totals/conc range 1 NR 518 0.008 to 90 69 0.3 to 37 596 0.2 to 42

Abbreviations: NR, not reported; Totals, rinse-off þ leave-on product uses.

a
Because each ingredient may be used in cosmetics with multiple exposure types, the sum of all exposure type uses may not be equal to sum of total uses.

275
276S International Journal of Toxicology 31(Supplement 3)

Results from another inhalation study identified the fol- Approximately 1% of the radiolabel remained in the carcasses
lowing 8 principal urinary metabolites of isooctane in the and tissues of both male and female rats.
urine of male Fischer 344 rats: 2,2,4-trimethyl-1-pentanol; Relatively little radioactivity was detected in the tissues at
2,4,4-trimethyl-1-pentanol; 2,4,4-trimethyl-2-pentanol; 72 hours, However, kidney levels of radioactive isooctane
2,2,4-trimethyl-l-pentanoic acid; 2,4,4-trimethyl-l- indicated a pronounced sex difference; male rats retained
pentanoic acid; 2,4,4-trimethyl-2-hydroxy-1-pentanoic acid; approximately 10-fold greater amounts of radioactivity than
2,2,4-trimethyl-5-hydroxy-1-pentanoic acid; and female rats. Less than 0.02% of the dose was detected in the
2,4,4-trimethyl-5-hydroxy-1-pentanoic acid.33 brain, heart, spleen, fat, lung, and liver, with no apparent sex
differences. Analysis of whole body autoradiography of isooc-
tane at 72 hours confirmed that the majority of the radioactivity
Isooctane—Oral Dosing in the male rat was localized in the kidney, with minor amounts
The metabolism of 14C-isooctane was studied using 8 groups of in the peritoneal fat. Autoradiography results indicated that the
male Fischer-344 rats (3 per group).7 The animals were dosed by radioactivity detected in the kidney was associated with the
oral gavage at a dose level of *1 mL/kg (2.9  107 DPM/kg). renal cortex.35
Most of the radioactivity was recovered in the urine and In another study, male and female Fischer 344 rats received
feces after 72 hours, with much of this excretion occurring a single oral dose of 14C-isooctane (4.4 mmol/kg; 2 pCi/mmol),
between 24 and 72 hours. More than one-third of the dose was and radiolabeled material in the kidney, liver, and plasma was
detected (and identified as unmetabolized isooctane) in exhaled determined at 4, 8, 12, 24, and 48 hours after dosing. The
air after 24 hours; essentially no additional lung excretion maximum concentration of isooctane-derived radioactivity in
occurred between 24 and 72 hours. Approximately 2.5% of the the kidney, liver, and plasma of male rats was found after
dose remained in the tissues after 72 hours. Meaningful blood 12 hours (1252, 1000, and 403 nmol eq/g, respectively); max-
levels of isooctane were not found; however, plasma radioac- imum concentrations in females were found after 8 hours (577,
tivity indicated the presence of circulating metabolites. Tissue 1163, and 3 17 nmol eq/g, respectively). A selective retention
concentrations of radioactivity indicated initial accumulation of the isooctane-derived radiolabel in the kidneys of male rats
in the liver over the first 8 hours, followed by a decline in liver was noted when peak tissue concentration was expressed as a
radioactivity. A high concentration of radioactivity was percentage of administered dose. Kidney concentrations of
detected in the kidney, surpassing the liver by 12 hours. A isooctane-derived radiolabel increased in a nonlinear, but
maximum was reached at 24 hours, and levels declined slowly dose-dependent, manner. 2,4,4-Trimethyl-2-pentanol was the
thereafter. The authors suggested that tissue and plasma levels major metabolite detected in the male rat kidney but was absent
were consistent with liver formation of metabolites, followed from the female rat kidney. However, compared to males,
by transport to the kidney in blood plasma and concentration or female rats excreted more conjugates of 2,4,4-trimethyl-2-
accumulations in the kidney.7 pentanol in the urine.36
Sexually mature male and female Fischer 344 rats were
dosed by gavage (5 mL/kg) with a single dose of C9 to C14 Isoalkanes/Isododecane
3
H-isooctane, in corn oil, at 4.4 mmol/kg and 230 mCi/kg. The
kidneys of male rats retained more radiolabeled material than Under the provisions of the Registration, Evaluation, Author-
those of female rats. Subcellular fractionation of the kidneys of ization, and Restriction of Chemical Substances (REACH)
male rats at 24 hours postdosing showed that approximately regulation in Europe, metabolism data on C9 to C14 isoalkanes
60% of the radiolabeled material was localized in the 116 000 g were summarized in a chemical safety report on isododecane.37
supernatant. Gas chromatography–mass spectrometry of an According to this report, C9 to C14 isoalkanes are taken up into
ethyl acetate extract of the a2u-globulin-containing fractions the blood, distributed to the internal organs, and rapidly elim-
of the 116 000 g supernatant identified 2,4,4-trimethyl-2- inated following exposure. The concentration of isoalkanes in
pentanol as the only metabolite bound to a2u-globulin.34 The the blood, brain, liver, and fat increases with increasing carbon
role of this protein in nephrotoxicity is mentioned under that chain lengths. These findings are consistent with other meta-
subheading. bolism data on isoparaffins included in this section.
Adult Fischer 344 rats of both sexes were given 5 mCi of
[14C-5]-isooctane (0.5 g/kg oral dose).35 Whole body and Animal Toxicology
kidney autoradiography were performed using [14C-5]-isooc-
tane (50 m Ci/rat) at the same dose. At an oral dose of 0.5 g/kg, Single-Dose Toxicity
exhaled organics (presumably the parent compound) accounted Inhalation. The lethal concentration was greater than the
for 45% to 50% of the dose in both males and females. There highest concentration generated in each acute inhalation study
were no differences between the sexes in percentages of the on a number of isoparaffins as summarized in Table 7.
administered dose excreted in the urine, feces, or as expired
CO2. A small percentage of the radioactivity was associated Oral. Isododecane had an oral median lethal dose (LD50) of
with exhaled CO2, indicating that minimal terminal carbon >2 g/kg in mice and other isoparaffin mixtures had oral LD50
oxidation on the isooctane molecule had occurred. values >10 g/kg in rats as summarized in Table 8.
Jr et al 277S

Table 7. Acute Inhalation Toxicity Studies on Isoparaffins and Isooctane.

Predominant
Material carbon length Animals Procedure Results

Isopar E C8-9 Mice Not stated Death at highest concentration

(8000 ppm).28
Isopar G C10-11 Rats Not stated 4 hours LC50 > 2000 ppm (12.2
mg/L).6
Isopar C 85% isooctane 10 male Swiss albino mice, 10 41-Minute exposure to near All animals died.7
male Wistar rats, and 10 saturated vapors
English short-hair guinea pigs
Isopar C 85% isooctane 10 CD-1 mice, 10 Sprague- 4–Hour exposure to 39.63 All animals died.7
Dawley rats, and 10 Hartley mg/L air
guinea pigs of both sexes
Isopar C 85% isooctane 6 Sprague-Dawley rats 4-Hour exposure to 21.0 Low incidences of lung
mg/L air discoloration and dilated renal
pelves.7
Isopar L C11-13 Rats Not stated 4 hours LC50 > 715 ppm (5.01
mg/L).6
Soltrol 100 C9-11 Rats Not stated 4-Hour LC50 > 3684 ppm (21.4
mg/L).6
Soltrol 130 C10-13 Rats Not stated 6-Hour LC50 > 1227 ppm (8.2
mg/L).6
Shell Sol 71 C9-12 Rats Not stated 4-Hour LC50 > 592 ppm (3.83
mg/L).6
Isopar G C10-11 Mice Groups exposed for 30 No significant effects on
minutes to 300 ppm respiratory rate.6
(1834 mg/m3) or 420
ppm (2621 mg/m3).
Soltrol 130 C10-13 Dogs 4-Hour exposure to 1308 Transient toxic effects, but no
ppm (8.4 mg/L) deaths.6
Soltrol 130 C10-13 4 dogs 6-Hour exposure to 221 ppm Death in 3 of 4 dogs.6
(14.2 mg/L)
Soltrol 130 C10-13 10 guinea pigs 4-Hour exposure to 1541 Lethargy in all 10 guinea pigs. No
ppm (9.9 mg/L) unusual findings at necropsy.6
Soltrol 130 C10-13 4 monkeys 6-Hour exposure to 1806 Retching and eye rubbing in all 4
ppm (11.6 mg/L) monkeys, but no deaths.6
Isooctane C8 Rats 4-Hour exposure LC50 > 14.38 mg/L.8
Isooctane C8 Rats 1-Hour exposure LC50 ¼ 47.4 mg/L.38
Isooctane C8 Rats (males and females) 4-Hour exposure LC50 ¼ 37.5 mg/L (males) and
34.7 mg/L (females).38
Isoctane C8 Mice 4-Hour exposure LC50 > 39.3 mg/L.38
Isoctane C8 4 SPF Mice 10-Minute exposure to No respiratory irritation.6
3000 ppm
Abbreviation: LC50, lethal concentration 50.

Dermal. Isoparaffin mixtures of various chain lengths (5.48 g/m3) C10-11 isoparaffin 5 days per week (6 h/d) for a
resulted in dermal LD50 values of >2 g/kg in rats as summar- total of 8 weeks.39 The ability of males to concentrate urine was
ized in Table 9. decreased following 4 and 8 weeks of exposure; evidence of
recovery was observed 4 weeks after the cessation of exposure.
Intraperitoneal. In an acute intraperitoneal (ip) toxicity study, Additionally, compared to controls, the urinary excretion of
rats (15/dose) were dosed with isooctane (in vegetable oil), glucose, protein, and epithelial cells in male rats was increased
followed by a 14-day observation period. An LD50 of 2375 following 4 and 8 weeks of exposure. Decreased creatinine
mg/kg was reported.38 clearance was observed after 8 weeks. All of these changes,
considered mild, returned to normal after 4 weeks of recovery.
Microscopic changes in the kidneys of exposed males (both
Repeated-Dose Toxicity groups) included an increased incidence of regenerative tubular
Inhalation epithelia and tubules dilated at the corticomedullary junction,
C10-11 isoparaffin. Groups of 50 male and 50 female Fischer with proteinaceous debris in the tubules; structural recovery
344 rats were exposed to 0, 300 (1.83 g/m3), or 900 ppm was not complete at the end of the 4-week recovery period.
278S International Journal of Toxicology 31(Supplement 3)

Table 8. Acute Oral Toxicity Studies on Isoparaffins and Isooctane.

Material Predominant carbon length Animals Results

Isopar G C10-11 Rats LD50 > 10 g/kg6

Isopar L C11-13 Rats LD50 > 10 g/kg6
Isopar C 85% isooctane Groups of 5 male albino rats LD50 > 10 000 mL/kg7
Soltrol 100 C9-11 Rats LD50 > 34.6 g/kg6
Soltrol 130 C10-13 Rats LD50 > 34.6 g/kg6
Shell Sol 71 C9-12 Rats LD50 > 25 g/kg6
Permethyl 99A C12 Rats LD50 > 5 g/kg103
Isododecane (10% in olive oil) C12 5 mice LD50 > 2 g/kg79
Isohexadecane C16 90 rats (males and females) LD50 > 46.4 mL/kg (>3.57 g/kg)104
Isooctane C8 Rats LD50 > 5 g/kg8
Isooctane C8 15 male rats/dose LD50 > 2.5 g/kg38
Abbreviation: LD50, median lethal dose.

Table 9. Acute Dermal Toxicity Studies on Isoparaffins and Isooctane.

Predominant
Material carbon length Animals Results

Isopar G C10-11 Rabbits LD50 > 3.2 g/kg6

Isopar L C11-13 Rabbits LD50 > 3.2 g/kg6
Isopar C 85% isooctane Groups of 4 albino rabbits LD50 >3160 mL/kg. Transient erythema/
(males and females) desquamation at application sites (intact
abdominal skin)7
Soltrol 100 C9-11 Rabbits LD50 ¼ 15.4 g/kg6
Soltrol 130 C10-13 Rabbits LD50 ¼ 15.4 g/kg6
Shell Sol 71 C9-12 Rabbits LD50 > 5.0 g/kg6
Isooctane C8 Rabbits LD50 > 2.0 g/kg8
Isooctane C8 5 rats (males) LD50 > 1000 mL/kg (ca. ¼ 70 mg/kg). No deaths or
signs of toxicity38
Isooctane C8 Groups of 4 New Zealand LD50 > 3.16 g/kg. After application to abraded
white rabbits abdominal skin, dark livers and mottled kidneys
at necropsy7

Abbreviation: LD50, median lethal dose.

Neither functional nor microscopic renal changes were unremarkable. However, slight lymphocytopenias and neutro-
observed in female rats. philia were observed in the differential leukocyte count at both
In another study, 3 groups of 15 Fischer 344 rats/sex were the midpoint and end of the study. There were also no remark-
exposed (inhalation) to the same concentrations of C10-11 able changes in behavioral patterns, body weight, or food
isoparaffin according to a similar 8-week test procedure.40 consumption.
An increased incidence of protein droplets was found in the
cytoplasm of renal tubular cells of male rats. Other renal C5-8 isoparaffin. Groups of Sprague-Dawley rats (12/sex per
changes (both exposures) included foci of regenerative epithe- group) were exposed to light alkylate naphtha (concentrations
lium and tubular dilatation, with intratubular protein occurring up to 6646 ppm) 5 days per week (6 h/d) for 13 weeks.41 Light
between the inner and outer stripe of the medulla. After 20 and alkylate naphtha is a substance described as containing >95%
40 days of exposure, focal loss of the brush border, with degen- isoparaffins with carbon numbers predominantly in the C5-C8
eration and sloughing of necrotic cells, was evident. Reversal range. Other than alpha 2u-globulin–mediated effects on the
of the exposure-related tubular changes was noted at the end of male rat kidney, the only effect reported was increased liver
the 4-week recovery period. Renal changes were not observed weight (males and females) in the 6646 ppm exposure group.
in female rats. There were no pathological changes in the liver, and the NOEL
for subchronic toxicity was 2220 ppm. A neurological exam-
C10-13 isoparaffin (Soltrol 130). In a short-term study, 4 rhe- ination was also performed, and the NOEL for neurotoxicity
sus monkeys were exposed to Soltrol 130 (mean exposure con- was 6646 ppm.
centration ¼ 654 ppm [4.2 mg/L]) 3 days per week (6 h/d) for a
total of 13 exposures.6 None of the animals died. Clinical C8-9 isoparaffin (Isopar E). A study was conducted to evaluate
chemistry, urinalysis, and gross and microscopic findings were the behavioral effects of Isopar E in groups of 8 adult male
Jr et al 279S

CFW albino mice.28 Static exposure chambers were used for cell volume, and total erythrocyte counts, was noted in males of
mice tested in the functional observational battery, one of the all exposure groups.
behavioral test methods used. Vapor exposures were conducted Increased spleen weights were observed in male rats of the
in 29 L cylindrical jars, and all vapor exposures were 30 min- high-exposure group. Liver weights were increased in males of
utes in duration. Three groups of mice were exposed to the high-exposure group and in males and females of the inter-
concentrations of 2000, 4000, and 6000 ppm, respectively. A mediate- and high-exposure groups. However, in the absence
fourth group was exposed to air only. Isopar E produced few of histological changes, these changes in organ weight were
effects over the range of concentrations tested, with most regarded as adaptation rather than as a toxic effect. Increased
effects being observed at the highest test concentration (6000 kidney weights were observed in males of all exposure groups,
ppm). Results of the functional observational battery conducted and these weight changes were accompanied by hyaline intra-
during the last 2 minutes of solvent exposure indicated that cytoplasmic inclusions, an increased incidence of tubular
Isopar E induced decreases in central nervous system activity degeneration and/or dilatation in the cortical tubules. Increased
(ie, arousal), muscle tone/equilibrium (ie, gait, mobility, and kidney weights were also observed in females of the high-
landing foot splay), and sensorimotor reactivity (ie, approach exposure group, in the absence of any exposure-related kidney
response). Exposure to a higher concentration of Isopar lesions. The low-grade anemia and mild renal degenerative
E (8000 ppm) caused death due to convulsions. changes were considered related to Shell Sol TD exposure and
biologically significant.6
C10-11 isoparaffin (Isopar G). The subchronic inhalation toxi-
city of Isopar G was evaluated using groups of 35 male and 35 Isooctane. Two groups of 70 Sprague-Dawley rats were
female Sprague-Dawley rats.42 The groups were exposed exposed, by inhalation, to Isopar C (85% isooctane) at cumu-
(inhalation) to 0, 300 (1.91 g/m3), or 900 ppm (5.62 g/m3) lative mean exposure concentrations of 385 and 1180 ppm,
Isopar G 5 days per week (6 h/d) for a total of 12 weeks. respectively.7 A third group served as the untreated control and
Decreased body weight was noted in male rats exposed to received sham air exposures. Each group consisted of 35 males
300 and 900 ppm. A concentration-related increase in absolute and 35 females. The animals were exposed to the test substance
and/or relative kidney weight was observed in male rats from 5 days per week (6 h/d) for 12 weeks. No treatment-related
300 and 900 ppm exposure groups and in female rats exposed mortalities occurred in the study. Body weights for control and
to 900 ppm. test animals were comparable and unremarkable. Some of the
Kidney tubule damage (male rats only) was described as hematocrit, hemoglobin, and red cell values were significantly
mild, but a concentration- and duration-related increase in depressed, compared to control values; however, all values
severity was noted. Also damage to the kidneys of male rats were within the biological limits. Of the clinical chemistry
was essentially comparable at 8 and 12 weeks. An increase in parameters evaluated, an elevated blood urea nitrogen level
both absolute and relative liver weight was observed in male in the 385 ppm exposure group was the only finding that may
and female rats exposed to 900 ppm; however, there was no have indicated a slight treatment-related response.
microscopic evidence of liver damage. Furthermore, this Compared to controls, an analysis of absolute and relative
change was considered representative of a nonspecific meta- organ/body weight ratios indicated an increase in both absolute
bolic and/or physiological response to the uptake of hydrocar- and relative mean kidney weights at 1180 ppm (males, week 8)
bon. Study results indicated that subchronic exposure to Isopar and at both 385 and 1180 ppm (males, week 12). These changes
G at doses up to 900 ppm did not induce significant toxic in organ weight were considered treatment related. At micro-
effects, other than mild structural changes in the kidneys of scopic examination, mild tubular injury at 8 and 12 weeks was
male rats.42 observed in some of the male rats exposed to 1180 ppm. All
other necropsy findings were considered unremarkable.7
C10-12 isoparaffin (Shell Sol TD). In another subchronic study, Wistar rats (number not given) were exposed to isooctane
male and female rats were exposed (inhalation) to Shell Sol TD vapor (10.3 or 24.2 mg/L; 4 h/d) for 5 days.38 None of the
at the following concentrations: 359 (2.53), 737 (5.20), or animals died during the 14-day observation period (LD50 >
1444 ppm (10.19 g/m3).6 A nonexposed control group was also 24.2 mg/L). Signs of toxicity included sedation and impeded
included. Groups were exposed 5 days per week (6 h/d) for a breathing. Rats (10 males, 10 females) were exposed to isooc-
total of 13 weeks. Neither deaths nor clinical signs occurred in tane vapor (9.66 mg/L, 6 h/d) 5 days per week for 12 weeks.38
both the low and intermediate dose groups. Rats in the high An untreated control group was also included in this study
exposure group became slightly lethargic. Aspartate amino- protocol. There were no clinical signs or hematological/macro-
transferase and alanine aminotransferase levels were decreased scopic findings. Increased relative kidney weights were noted;
in females of all exposure groups, whereas alkaline phospha- however, the results of liver and kidney function tests were
tase, potassium, chloride, and albumin were increased only in unremarkable. Decreased body weight gain was noted in male
males of the high-exposure group. Changes in the levels of rats only.
these enzymes, ions, and so on were considered minor and their
toxicological significance remains unknown. A low-grade ane- Isododecane. In a subchronic inhalation toxicity study,
mia, characterized by slight reductions in hemoglobin, packed groups of rats (20 males, 20 females/group) were exposed to
280S International Journal of Toxicology 31(Supplement 3)

atmospheres containing 0, 200 (1.4 air), 600 (4.2), or 1800 ppm administered by oral gavage (dose volume ¼ 1.0 mL/kg) to the
(123.6 g/m3) 5 days per week (6 h/d) for 13 weeks.43 Growth 5 test groups on consecutive days as follows: group 1 (1 day),
retardation and a transient reduction in red blood cell counts group 2 (3 days), group 3 (7 days), group 4 (14 days), and group
were noted in males and females exposed to 1800 ppm isodo- 5 (21 days). Similarly, control groups were dosed with distilled
decane. When compared to control rats, both the degree and water on consecutive days. A 90-min pulse label (ip) with
3
incidence of inflammatory reactions in the respiratory tract H-thymidine, followed by extraction of DNA from the liver
appeared to have been lower for males in the 1800 ppm expo- and kidney was used to determine new DNA synthesis. Com-
sure group and for females in the 600 and 1800 ppm exposure pared to controls, kidney-to-body weight ratios were signifi-
groups. Increased plasma alkaline phosphatase activity was cantly greater in treatment groups at 3, 14, and 21 days of
reported only for female rats at this level of exposure. dosing. By day 21, kidney weight ratios were 29% greater in
Relative kidney weights were increased in rats of both sexes treatment groups. Liver-to-body-weight ratios were signifi-
exposed to 1800 ppm and in male rats exposed to 600 ppm. At cantly higher at 3, 7, 14, and 21 days; ratios were 61% higher
necropsy, there appeared to have been an increased incidence by day 21. Both the liver and kidney showed an increase in
of green kidneys following exposure to 1800 ppm. Microscopic relative organ weight and a concomitant decrease in DNA con-
examination confirmed a dose-related increase in the incidence tent, with the liver showing the greater effect. It was noted that
of tubular nephrosis in male rats. Data relating to effects on the much of the decreased DNA content could be accounted for by
reproductive system are included in the Reproductive and the relative increase in organ weight.
Developmental Toxicity sectionlater in the report text. It was Daily dosing with isooctane resulted in stimulation of DNA
concluded that the no-adverse-effect level of isododecane in turnover in the kidney. This effect was maximal ranging from
rats was <200 ppm.43 7 to 14 days of dosing, when 3H-thymidine incorporation into
DNA was 4-fold greater when compared to controls. On the
Oral other hand, the liver only showed stimulation of DNA turnover
Isooctane. According to the US Environmental Protection following 1 day of dosing, and subsequent dosing did not pro-
Agency (EPA), an oral reference dose (RfD) is an estimate of duce a significant effect. It was noted that these results are
a daily oral exposure to the human population that is likely to consistent with the findings that the kidney is the target organ
be without appreciable risk of deleterious effects during a for isooctane and compounds in this class.7
lifetime.44 Groups of 5 male Fischer 344 rats received oral doses of
The EPA noted that a number of acute and short-term stud- isooctane (50-500 mg/kg) by gavage for 21 days.45 The animals
ies have been identified in the literature, but that these studies were injected ip with [CH3-3H]-thymidine on day 22, and sites
are limited, in that they were designed to only investigate end of renal cell proliferation induced by isooctane were localized
points specific to a2u-globulin–associated nephropathy in male and quantitated using histoautoradiographic analysis. Light
rats. Detailed studies on isooctane (2,2,4-trimethylpentane) that microscopic lesions in the proximal convoluted tubule con-
identify sufficient dose–response and duration information for sisted of protein droplet and crystalloid body accumulation,
other end points are lacking. The available studies provided degeneration, and necrosis. These renal lesions were not dose
evidence that the kidney toxicity induced by isooctane in male related, but a finding of tubular dilation of the thin segments
rats is related to a2u-globulin accumulation in the proximal with granular cell debris was dose related.
tubules (a response that is specific to male rats). EPA con- Isooctane induced a nondose-related, 5- to 6-fold increase in
cluded that this end point is not appropriate for determining the labeling index of the same proximal convoluted tubule
noncarcinogenic hazard. No other studies were considered suit- portions (P2 segment) that contained severe crystalloid body
able for the derivation of an RfD, and, therefore, an oral RfD accumulation, degeneration, and necrosis. Less pronounced,
for chronic oral exposure was not derived.44 but statistically significant (P  .05), increases in cell prolif-
eration were also observed in other nephron segments, indica-
Nephrotoxicity tive of a generalized regenerative response of the kidney to
Isooctane. Renal function changes were evaluated in a study isooctane. It was noted that the cytotoxic and regenerative
involving Fisher 344 rats (sex not stated).12 Groups of 4 rats effects of oral dosing with isooctane suggest that similar
were dosed orally with isooctane (in corn oil) at a dose of 0.1 or mechanisms may be involved in the induction of kidney tumors
0.5 g/kg per d for 4 weeks (5 times/week). Groups of 3 rats in male rats exposed (chronic inhalation) to unleaded gaso-
served as controls (corn oil). A statistically significant decrease line.45 The observed isooctane-induced increase in cell prolif-
in the inulin clearance (marker for glomerular filtration rate eration in nephron segments is also mentioned briefly in the
[GFR]) was observed after 2 and 4 weeks of gavage with Carcinogenicity section later in the report text.
0.5 g/kg per d. The decrease in GFR was more profound at 4 The EPA has made an effort to derive a reference concen-
weeks than at 2 weeks. A significant increase in the urinary tration for isooctane chronic inhalation exposure (RfC).44 The
enzyme, N-acetyl-beta-glucosaminidase (at 2 and 4 weeks) was RfC (mg/m3), analogous to the RfD, takes into consideration
associated with this reduction in the GFR. toxic effects for both the respiratory system (portal of entry)
The nephrotoxicity of isooctane was evaluated using groups and the effects peripheral to the respiratory system (extrare-
of 8 male Fischer-344 rats.7 The undiluted test substance was spiratory effects). The EPA noted that a2u-globulin–associated
Jr et al 281S

nephropathy was observed in a repeated-dose inhalation study a2u-globulin were detected in a study involving NCI-Black-
on isooctane, providing evidence that the kidney toxicity Reiter male rats receiving isooctane (in corn oil) at daily oral
induced by this chemical is related to a2u-globulin accumula- doses of 500 mg/kg. The NCI-Black-Reiter rat is the only strain
tion in the proximal tubules. The EPA concluded that this end of male rat that is known not to synthesize the hepatic form of
point is not appropriate for determining noncarcinogenic the low-molecular-weight protein a2u-globulin. In the absence
hazard. No other studies were considered suitable for the deri- of this protein, isooctane did not induce kidney injury, and
vation of an RfD, and, therefore an inhalation RfC was not these data provide further support for the role of a2u-globulin
derived. in nephrotoxicity.50

Nephrotoxicity/Hepatotoxicity
Isooctane. The potential for isooctane-induced nephrotoxi- Ocular Irritation
city or hepatotoxicity was evaluated using groups of 6 male
Wistar albino rats.46 The test substance (in corn oil [2:1]) was Isooctane. In a chemical safety report that was prepared in
administered by gavage at a single daily dose of 2 mL/kg. accordance with the REACH regulation, isooctane was not
Control rats received a similar volume of corn oil alone. After irritating to the eyes of rabbits.51 This finding is consistent with
2 days of treatment, all test rats had signs of toxicity and had ocular irritation study results for other isoparaffins included
lost a considerable amount of weight. Thus, 6 control animals below.
and all treated animals were killed by the third day. Macro-
Isohexadecane and isododecane. The EpiOcular human cell
scopic examination of the kidneys revealed no visible lesions;
construct (EOT) was used to assess the ocular irritation poten-
however, white patches (slightly raised) on the liver were found
tial of a tan-enhancing spray containing 42% isohexadecane.
in 2 rats.
The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazoliumbro
Centrilobular and confluent necrosis, hydropic degenera-
mide (MTT) conversion assay was used to assess cellular
tion, and vaculolation of hepatocytes were noted at micro-
metabolism by EOT following product exposure. This assay
scopic examination. Analysis of plasma alkaline phosphatase
measures the nicotinamide adenine dinucleotide phosphate-
and aspartate transaminase activity revealed increases that are
oxidase–dependent microsomal enzyme reduction of MTT,
consistent with liver damage. Microscopic examination of the
and, to a lesser extent, the succinate dehydrogenase reduction
kidneys revealed eosinophilic hyaline droplet accumulation in
of MTT, to a blue formazan precipitate. The duration of
cells of the tubules and tubular dilation. Analysis of urinary
exposure resulting in a 50% decrease in MTT conversion
N-acetyl-B-glucosaminidase and alkaline phosphatase activity
(ET50) in product-treated EOTs, relative to controls, was
showed increases that are consistent with renal toxicity. Based
determined. An ET50 of 698.25 min (no/minimal irritation) was
on the results of this study, the authors noted that it would
reported for the tan-enhancing spray containing 42%
appear that isooctane possess hepatotoxic as well as nephro-
isohexadecane.52
toxic properties.46
In the in vitro hens’s egg test, EXP-SR5 (contains 55.5%
isohexadecane, 35% isododecane),53 permethyl 216C (contains
Nephrotoxicity Mode of Action in Rats 40% isohexadecane),54 permethyl 284C (contains 20% isodo-
decane),55 and permethyl 296C (contains 50% isododecane),56
While male rat nephrotoxicity observed after exposure to iso- were classified as negative for ocular irritation potential.
paraffins has been attributed to reversible binding of the hydro- Results for permethyl 222C (material containing 40% isoeico-
carbon to a2u-globulin, this mechanism of action is not relevant sane) indicated practically no irritation to slight ocular irrita-
in humans. tion.57 In this assay, the chorioallantoic membrane of the chick
Subchronic or chronic inhalation exposure to C10-12 embryo responds to injury with a complete inflammatory
isoparaffin at a concentration of 6.5 mg/L caused both reaction, comparable to that induced in the rabbit eye test.
functional and morphological renal changes in normal male In a chemical safety report that was prepared in accordance
Sprague-Dawley rats, but not female or castrated male rats of with the REACH regulation, isohexadecane was nonirritating
the same strain.47 Male rat nephrotoxicity has been attributed to to the eyes of rabbits.58 This finding is consistent with ocular
reversible binding of hydrocarbon to a2u-globulin, which is not irritation study results for other isoparaffins included in this
synthesized in humans.48 Based on the measurement of several section. Data on hydrocarbons, C10-C12, isoalkanes, <2% aro-
biochemical indicators of nephrotoxicity, isooctane (single oral matics in another chemical safety report were among the data
dose, 12 or 24 mmol/kg) in corn oil was not found to impair used to evaluate the ocular irritation potential of isododecane,
renal proximal tubular function in male-specific pathogen free and the results were negative in rabbits.37
rats of the Alderley park strain (Alpk/AP). There was a strong
association between the presence of renal hyaline droplets and Isoeicosane. In a chemical safety report that was prepared in
the occurrence of a2u-globulin at these doses; however, the accordance with the REACH regulation, data on hydrocarbons,
toxicological significance of increases in renal hyaline droplet C14-C18, n-alkanes, isoalkanes, cyclics, and 2% aromatics
formation was not established.49 Histopathological changes in were among the data used to evaluate the ocular irritation
the kidney were not observed, and neither hyaline droplets nor potential of isoeicosane, and results were negative in rabbits.59
282S International Journal of Toxicology 31(Supplement 3)

Table 10. Ocular Irritation Studies on Isoparaffins.

Predominant carbon
Material length Animals Test procedure Results

Isopar G C10-11 Rabbits Draize test. 0.1 mL instilled No corneal lesions. Draize
scores of 0 to 1 (max.
score ¼ 110)6
Isopar L C11-13 Rabbits Draize test. 0.1 mL instilled Slight conjunctival irritation,
but no corneal lesions.
Draize scores of 0 to 66
Soltrol 100 C9-11 Rabbits Draize test. 0.1 mL instilled Minimal, transient
conjunctival irritation6
Soltrol 130 C10-13 Rabbits Not stated Conjunctival redness and
discharge (grade 1), but no
corneal opacity6
Isododecane C12 Rabbits 0.1 mL instilled Nonirritant105
Isododecane C12 3 rabbits Not stated Nonirritant79
Permethyl 99A C12 6 rabbits 0.1 mL instilled Nonirritant106
Mixture of isododecane C12 isododecane 3 rabbits 20% isododecane tested Nonirritant79
(40%) and (C12)
trimethylsiloxysilicate
(60%) in olive oil
Isooctane C8 Rabbits 0.1 mL instilled Nonirritant7
Isohexadecane C16 6 rabbits 0.1 mL instilled Nonirritant107
Tan enhancing spray C12 MTT in vitro assay No/minimal irritation52
containing 42%
isohexadecane
EXP-SR5 C12, C16 Hen’s egg test in vitro Nonirritant53
Permethyl 216C C16 Hen’s egg test in vitro Nonirritant54
Permethyl 222C C20 Hen’s egg test in vitro Nonirritant to slight irritant57
Permethyl 284C C12 Hen’s egg test in vitro Nonirritant55
Permethyl 296C C12 Hen’s egg test in vitro Nonirritant56
Abbreviations: MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide.

Ocular irritation study results are also summarized in Table 10. treated and control ear of one rabbit and on the treated ear of a
second rabbit. There was no evidence of comedone formation
Skin Irritation on treated or control ears of rabbits, and isododecane was
considered noncomedogenic.60 Permethyl 99A (isododecane)
Isoparaffins are generally slightly to moderately irritating to was also classified as noncomedogenic when tested according
skin. Summaries of skin irritation studies are included in Table to the same procedure.61
11. In a chemical safety report that was prepared in accordance
with the REACH regulation, isooctane was irritating to the skin
Isohexadecane. Permethyl 101A (isohexadecane) was classi-
of rabbits.51 This finding is consistent with skin irritation test
fied as noncomedogenic in rabbits when evaluated according to
results for other isoparaffins included in this section. In a chem-
the preceding test procedure.62
ical safety report that was prepared in accordance with the
REACH regulation, data on hydrocarbons, C16-C20, aliphatics,
and 2% aromatics were among the data used to evaluate the
skin irritation potential of isoeicosane, and results were nega- Skin Sensitization
tive in rabbits.59 Similarly data on hydrocarbons, C10-C12, iso-
C11-13 isoparaffin (Isopar L). Reportedly, in a guinea pig
alkanes, and <2% aromatics in another chemical safety report
sensitization test, Isopar L was classified as a nonsensitizer.6
were among the data used to evaluate the skin irritation poten-
These data were referenced as unpublished data from Exxon
tial of isododecane, and results were negative in rabbits.37
Cooporation and study details were not included.

Comedogenicity Isooctane. In a chemical safety report that was prepared in

Isododecane. Isododecane was applied undiluted to the ear of accordance with the REACH regulation, data on hydrocarbons,
each of 3 New Zealand White rabbits for 3 consecutive weeks C7-C9, n-alkanes, isoalkanes, and cyclic were used to evaluate
(5 days/week). The right ear served as the untreated control. At the skin sensitization potential of isooctane, and results were
microscopic examination, hyperkeratosis was observed on the negative.51
Jr et al 283S

Table 11. Skin Irritation Studies on Isoparaffins Using Rabbits.

Predominant carbon Number of

Material length animals Doses tested Procedure Results

Isopar G C10-11 NAa Not stated 24-Hour contact period Slight dose-related skin
irritation6
Isopar G C10-11 NA Undiluted Occlusive patch test Primary irritant (grade 5)6
Isopar G C10-11 NA Undiluted Modified nonocclusive patch test Nonirritant6
Isopar L C11-13 NA Not stated Not stated Slight skin irritation6
Soltrol 100 C9-11 NA Not stated Applied to intact or abraded skin Mild skin irritation
Soltrol 130 C10-13 NA Not stated Draize test Primary irritant (grade
5.7)6
Soltrol 130 C10-13 NA Not stated Applied to intact or abraded skin Very slight to severe
irritation6
Shell Sol 71 C9-12 NA Not stated Not stated Moderately irritating6
Isododecane C12 6 rabbits Undiluted—0.5 mL/ 24-Hour contact period Mildly irritating108
2.5 cm2
Isododecane C12 3 rabbits Undiluted Cumulative irritation test Mild irritant79
Isododecane C12 3 rabbits 50% in petrolatum Primary irritation test Mild irritant79
Permethyl C12 6 rabbits Undiluted—0.5 mL/ 24-Hour contact period Mildly irritating109
99A 2.5 cm2
Isohexadecane C16 6 rabbits 0.5 mL, 2.5  2.5 cm 24-Hour contact period Nonirritant110
patch
Isooctane C8 2 rabbits Not stated Ears painted twice daily for 5 Slight redness (short
consecutive days duration)6

Abbreviation: NA, not applicable.

Isododecane. In another chemical safety report that was Isooctane

prepared in accordance with the REACH regulation, data
The embryotoxic and/or teratogenic potential of Isopar C (85%
on hydrocarbons, C10-C12, isoalkanes, <2% aromatics and
isooctane) was evaluated using groups of 20 mated Sprague-
hydrocarbons, C10-C13, isoalkanes, and <2% aromatics were
Dawley rats.7 Two groups were exposed to the test substance at
among the data used to evaluate the skin sensitization
concentrations of 400 and 1200 ppm, respectively, on days 6 to
potential of isododecane, and results were negative in
15 of gestation. A negative control (air exposed) group and a
guinea pigs.37
positive control (acetylsalicylic acid orally, 400 mg/kg per d)
group were included. Female rats were killed on day 21 of
Isoeicosane. Similarly, in a chemical safety report that was
gestation, and fetuses were evaluated for external, soft-tissue,
prepared in accordance with the REACH regulation, guinea
and skeletal malformations.
pig maximization test data on C10-C12 isoalkanes, <2% aro-
Compared to controls, rats exposed to 400 or 1200 ppm Isopar
matics were among the data used to evaluate the skin sensiti-
C had a significantly higher implantation efficiency. However,
zation potential of isoeicosane, and results were negative in
this finding was not indicative of a treatment-related adverse
guinea pigs.59
effect. Also, in these 2 groups, there were no treatment-related
effects on the following: uterine implantation data, fetal size or
sex distribution data, or fetal external, soft-tissue, or skeletal
Reproductive and Developmental Toxicity examination data. The incidence of fetuses with ossification var-
iations was significantly increased in the 1200 ppm exposure
Isopar G (C10-11 Isoparaffin) group. However, the types and incidences of ossification varia-
Reportedly, in a reproductive toxicity study, mated Sprague tions were generally comparable to observations in the control
Dawley rats were exposed (inhalation, 6 h/d) to 0, 300, or group. It was concluded that Isopar C was neither embryotoxic
900 ppm Isopar G on days 6 to 15 of gestation.6 The dams nor teratogenic in Sprague-Dawley rats exposed at concentrations
were killed on day 21 of gestation, and fetuses were examined of 400 and 1200 ppm. The incidence of fetal malformations was
for external, visceral, and skeletal malformations. Compared to increased in the positive control group.7
controls, there were no changes in the following parameters: According to a chemical safety report that was prepared in
resorptions, fetal size, sex distribution, and fetal alterations. accordance with the REACH regulation, no reproductive
Isopar G was neither fetotoxic nor teratogenic to rats at con- effects are expected after exposure to isooctane.51 This expec-
centrations up to 900 ppm. These data were referenced as tation is based on negative results for hexane, a structurally
unpublished data from Exxon Company, and the number of related substance, in reproductive and developmental toxicity
animals per dose group was not included. studies.
284S International Journal of Toxicology 31(Supplement 3)

Isododecane epididymides, and prostate. It was concluded that Isopar C was

not mutagenic in the dominant-lethal test at doses of 400 and
Results from a subchronic inhalation toxicity study on isodo-
1200 ppm.7
decane, summarized earlier in the report text, indicated
increased relative weights of the gonads in male and female
rats exposed (inhalation) to 1800 ppm isododecane for Isododecane
13 weeks.43 The test protocol and other study results are In a chemical safety report that was prepared in accordance
included in the Subchronic Inhalation Toxicity section. with the REACH regulation, mammalian genotoxicity data
In a chemical safety report that was prepared in accordance on isododecane and bacterial and mammalian genotoxicity data
with the REACH regulation, data on hydrocarbons, C9-C12, on hydrocarbons, C10-C12 isoalkanes, and < 2% aromatics were
n-alkanes, isoalkanes, cyclic, and aromatics (2 to 25%) were used to evaluate the genotoxicity potential of isododecane, and
among the data used to evaluate the reproductive toxicity of results were negative.37
isododecane in rats and data on hydrocarbons, C9-C11, isoalk-
anes, cyclic, and <2% aromatics were among the data used to
evaluate the developmental toxicity of isododecane in rats.37
Carcinogenicity
Neither reproductive nor developmental toxic effects were
observed. Isooctane
Petrolatum (15% in isooctane [concentration not stated]) was
Isohexadecane and Isoeicosane applied to the skin in groups of 30 male and 30 female Swiss
Similarly, in chemical safety reports that were prepared in mice.63 Applications (3 drops, * 60 mL/application) were
accordance with the REACH regulation, data on hydrocarbons, made to dorsal skin twice weekly during lifetime treatment.
C16-C20, n-alkanes, isoalkanes, cyclic, and <2% aromatics were Survival of the mice was good and no significant tumor inci-
among the data used to evaluate the developmental toxicity of dence was found.
isoeicosane.58,59 The NOAEL was >1000 mg/kg per d, and Findings relating to isooctane-induced increases in cell pro-
there were no signs of maternal toxicity or treatment-related liferation in rat nephron segments are included in the section on
adverse effects on fetal development in rats. Nephrotoxicity/Cell Proliferation earlier in the report text.45
A study was performed to better characterize the pathogen-
esis of a2u-globulin nephropathy.64 Groups of 3 F344 rats per
sex were exposed (inhalation) to 10, 70, or 300 ppm unleaded
Genotoxicity gasoline or 50 ppm isooctane from 3 to 50 weeks (6 h/d, 5 days/
The following text includes additional details from the muta- week). Cell proliferation was quantitated within 3 proximal
genicity study on Isopar C (85% isooctane) summarized in tubule segments of the kidney (P1, P2, and P3). Immunohisto-
Table 12. In this study, the mutagenicity of Isopar C following chemical staining of a2u-globulin was performed on kidney
inhalation exposure was evaluated in the dominant lethal test sections. To determine whether accumulated a2u-globulin was
using groups of 10 male Sprague-Dawley rats, which were concentration related, the ranking of slides based on the sever-
subsequently mated with females.7 Two groups were exposed ity and extent of accumulation of crystalloid a2u-globulin dro-
(inhalation) to the test substance at concentrations of 400 and plets and single-cell necrosis of the affected P2 tubule was
1200 ppm, respectively. Male rats were exposed 5 days per performed. Results indicated significant increases in rank
week (6 h/d) for 8 consecutive weeks. Treatment was followed above age-matched controls in kidneys from male rats exposed
by a 2-week mating period. A negative control group (air to 300 ppm unleaded gasoline or 50 ppm isooctane at each
exposed) and a positive control group (triethylenemelamine exposure interval. Mild but detectable increases in a2u-globulin
[TEM], 0.5 mg/kg ip) were also included in the study. Mean staining were observed in groups exposed to 10 or 70 ppm
body weights were comparable between negative control and unleaded gasoline.
test groups. The largest increases in labeling indices (above controls)
The mating of females with TEM-positive control males occurred in the P2 segment, that is, 6- to 11-fold increases in
resulted in fewer implants and lower implantation efficiency labeling indices at 3, 10, and 22 weeks of exposure to 300 ppm
values (indicative of preimplantation loss), compared to unleaded gasoline or 50 ppm isooctane. These changes were
females mated with negative control males. There were no indicative of dose-related increases in cell turnover, and this
treatment-related effects on mortality, in-life physical observa- proliferative response closely paralleled the extent and severity
tions, or necropsy observations following exposure to 400 or of detectable a2u-globulin in the P2 segment. Neither a2u-glo-
1200 ppm. Pregnancy rates, implantation data, and implanta- bulin nor cytotoxicity was evident in cells of the P1 or P3
tion efficiency values and fetal death data for females mated to segment; however, in the P3 segment, cell proliferation was
males exposed to Isopar C were comparable to data for females increased (up to 8-fold) for up to 22 weeks of exposure. Com-
mated to negative control males. Microscopic evaluation of the pared to controls, increased numbers of proximal tubules
following tissues from 5 randomly selected males did not affected by chronic progressive nephrosis were found in males
reveal any treatment-related effects: testes, seminal vesicles, exposed to unleaded gasoline or isooctane for 22 or 48 weeks.
 Table 12. Genotoxicity of Isoparaffins and Isooctane.
Predominant
Material carbon length Strain/cell type Assay Dose Results
Isopar L C11-13 Salmonella typhimurium strains Reverse mutation assay with and Not stated Not mutagenic.6
TA98, TA 100, TA 1535, TA without metabolic activation
1537, and TA 1538
Isopar G C10-11 Salmonella typhimurium strains Reverse mutation assay with and Not stated Not mutagenic.6
TA98, TA 100, TA 1535, TA without metabolic activation
1537, and TA 1538
Soltrol 130 C10-13 Salmonella typhimurium strains Reverse mutation assay with and Doses up to 10 000 mg/ Not mutagenic.6
TA98, TA 100, TA 1535, TA without metabolic activation plate
1537, and TA 1538
Isopar G C10-11 Escherichia coli strain Pol A Pol Aþ A DNA repair assay Not stated Not genotoxic.6
Isopar G C10-11 Escherichia coli strain WP2 Reverse mutation assay with and Not stated Not mutagenic.6
without metabolic activation
Soltrol 130 C10-13 L5178Y mouse lymphoma cells Forward mutation assay with and Doses up to 1000 mg/ml Not mutagenic.6
without metabolic activation
Soltrol 130 C10-13 Chinese hamster ovary cells In vitro sister chromatid Doses up to those that Not genotoxic.6
exchange assay with and inhibited cell growth
without metabolic activation due to toxicity
Isopar G C10-11 Mice (erythrocytes evaluated) In vivo micronucleus assay ip dosing with Isopar G Not clastogenic.6
(25 mL/kg), given as 10%
solution in corn oil
Isopar G C10-11 Sprague-Dawley rats (germ cells In vivo dominant lethal test Inhalation exposure to Compared to controls, no
evaluated) concentrations up to treatment-related changes in
900 ppm pregnancy rate, number of
implantations, or numbers of
early or late fetal deaths. Not
mutagenic.6
Isopar C 85% isooctane (C8) Sprague-Dawley rats In vivo dominant lethal test Inhalation exposure Negative results.7
concentrations up to
1200 ppm
Isododecane C12 Salmonella typhimurium strains Doses of 156 to 5000 Negative results79
TA100 and TA98 mg/plate
Mixture of Isododecane C12 (isododecane) Salmonella typhimurium strains Ames test 156 to 5000 mg/plate Negative results79
(40%) and TA100 and TA98
trimethylsiloxy-silictate
(60%)
Isooctane C8 Rat and mouse hepatocytes In vivo and in vitro unscheduled Cells from rats and mice No UDS.68
DNA synthesis (UDS) assays dosed by gavage with
500 mg/kg isooctane
Isooctane C8 Mouse lymphocytes L5178Y TK+ mouse lymphoma Doses up to 0.5 mL/mL + Not mutagenic.111
assay for TK locus mutations metabolic activation
Isooctane C8 TK6 human lymphocytes TK6 mutation and sister 5% in medium (suspension Not genotoxic in both assays.66
chromatid exchange assays 100% saturated by
stirring); + metabolic
activation
Abbreviation: UDS, unscheduled DNA synthesis.

285
286S International Journal of Toxicology 31(Supplement 3)

McLaren et al,67 or stimulate unscheduled DNA synthesis in

CH2
a study by Loury et al.68
The US EPA concluded that there are no available chronic
(CH 3)3CCH2CCH2(CH3) 3 bioassays or epidemiological studies in humans that assess the
carcinogenicity of isooctane, and that this overall lack of infor-
Isododecane
mation represented a data gap and did not allow for a quanti-
tative assessment of the carcinogenicity of isooctane.44,69

(iso-C19H 39)-CH3
Isododecane
Isoeicosane
In a chemical safety report that was prepared in accordance
with the REACH regulation, data on the following chemicals
were among the data used to evaluate the carcinogenicity of
CH 3 CH3 isododecane37: Inhalation exposure to hydrocarbons, C10-C12
isoalkanes, and <2% aromatics (Stoddard solvent IIC) caused
(CH3) 3CCH 2CHCH 2CCH 2(CH 3)3 neoplastic effects in male rats and female mice. Dermal expo-
sure to Stoddard solvent and hydrocarbons, C10-C13, n-alkanes,
and <2% aromatics caused neoplastic effects in male mice.
CH 3 Regarding the inhalation study, it was noted that there was
no evidence of carcinogenic activity of Stoddard solvent IIC
Isohexadecane
in female F344/N rats or in B6C3F1 male mice exposed to 2200
mg/m3, and that the National Toxicology Program (NTP) con-
cluded that there was equivocal evidence of carcinogenic activ-
CH 3 ity of Stoddard solvent IIC in female B6C3F1 mice based on
increased incidences of hepatocellular adenoma. It was also
CH 3CCH 2CHCH 3 noted that the incidences of benign pheocoromocytoma in
550 and 1100 mg/m3 male rats and benign or malignant pheo-
chromocytoma exceeded the historical chamber control ranges,
CH 3 CH 3 suggesting that exposure to Stoddard solvent IIC caused the
increased incidences of these adrenal medulla neoplasms. The
Isooctane incidence of malignant pheochromocytoma was described as
one malignant tumor in control animals and 2 malignant tumors
Figure 1. Isoparaffin formulas. in 1100 mg/m3 male rats. However, it was stated that the rele-
vance of pheochromocytoma in humans is equivocal at best.
These lesions contained epithelial cells that were highly pro- These carcinogenicity data could be considered along with
liferative. Neither a2u-globulin nephropathy nor increases in other available data in evaluating the carcinogenicity of
P2 or P3 cell turnover were observed in control or treated isoparaffins.
female rats. The authors noted that the results of this study
suggest that chronic cell proliferation associated with a2u-glo-
bulin nephropathy and chronic progressive nephrosis in male Isohexadecane and Isoeicosane
rats exposed to unleaded gasoline or its isoparaffinic compo- According to chemical safety reports on isohexadecane and
nents, such as isooctane, may be responsible for nephrocarci- isoeicosane that were prepared in accordance with the REACH
nogenic effects of unleaded gasoline in male rats.64 regulation, hydrocarbons, C14-C20 aliphatic, and <2% aro-
The majority of the reported studies contribute information matics are metabolized and excreted rapidly, are not genotoxic,
specifically related to the histopathological sequence of and there is no evidence from the repeat-dose studies that they
a2u-globulin-associated nephrotoxicity. Thus, these studies do are able to induce hyperplasia or preneoplastic lesions.58,59
not examine any other tissue/organ except the kidney. In com- Thus, it is highly unlikely that these chemicals would be carci-
paring the tumor-promoting capability between isooctane and nogenic. These data were used to evaluate the carcinogenicity
unleaded gasoline (UG, a mixture), Short et al65 showed that of isohexadecane and isoeicosane.
both agents had promoting potential in male, but not female
rats. However, the results were not sufficiently descriptive to
ascribe the portion of the promoting potential of UG that could Tumor Promotion
be attributable to isooctane. The few studies available on its Isooctane. An initiation-promotion study was performed
genotoxic potential were negative, as isooctane does not using 30 Fischer 344 rats/sex per experiment. Rats were given
increase mutations at the TK locus in a study by Richardson N-ethyl-N-hydroxyethylnitrosamine (170 ppm) in drinking
et al, 66 induce DNA double-strand breaks in a study by water for 2 weeks, followed by a 2-week nontreatment
Jr et al 287S

period.65 The rats were then exposed to isooctane via inhalation (6 h/d), and 5 participants served as nonexposed controls. Com-
(50 ppm [* 2.4 mg/L],6 h/d) 5 days per week for 24 or 59 to 60 pared to controls, significant differences in creatine kinase and
weeks. Decreased kidney weights were noted in male rats only, follicle-stimulating hormone were noted following exposure. It
and incidences of atypical cell foci (ACF) and renal cell tumors was noted that there was marked intraindividual and interindi-
(RCTs) were 79% and 14%, respectively, in these animals. vidual variability in the serum concentrations of these para-
Incidences in control rats were 35% (ACF) and 4% (RCT), and meters. There was no evidence of changes in plasma
the differences between test and control rats were not found to immunoglobulin or orosomucoid.74
be statistically significant. Female rats had normal kidney
weights, and there were no increases in ACF or RCT.
Ocular Irritation
Cell Proliferation C11-12 isoparaffin. The ocular acceptability of a mascara
containing 48.28% C11-12 isoparaffin was evaluated using
HeLa cell (S3 cell line) suspensions were exposed to isooctane 48 female participants. The product was applied to the eye-
at concentrations ranging from 0.1% to 7.5% and examined for lashes twice daily (morning and early afternoon) for 4 weeks
morphological changes associated with toxicity.70 Cultures and was considered well tolerated. Nine participants presented
were incubated for 2 to 3 days at a temperature of 37 C. The with the following subjective signs, described as being of slight
overall physiologic state of the cells after exposure was quan- intensity and of very short to long (1 day) duration: general
tified, in terms of the intracellular adenosine triphosphate sensation of irritation, ocular stinging, palpebral stinging,
(ATP) concentration, using a chemiluminescence ATP assay. sensation of foreign body, discomfort, and sensation of dryness
There was no obvious effect on cell proliferation, for example, and tightness). One participant presented with subjective signs
the absence of mitotic figures was not noted after day 1 of (ocular stinging) that were of slight intensity and very short
exposure. Additionally, there was no evidence of differences duration. These signs were frequent and said to have been
in cell shape, granularity around the nucleus, or visible damage probably due to mascara.75
to the cell membrane. Other results indicated that exposure to
isooctane produced little change in the intracellular ATP Isododecane. In another ocular acceptability study, a mascara
concentration. containing 63.7% isododecane was evaluated using 10 female
participants. The product was applied to the eye lashes once
daily for 5 days and there was no evidence of ocular irritation.76
Clinical Assessment of Safety When the test procedure was repeated in another study (same
C8-12 Isoparaffin (Shell Sol TD) product, 50 females) over a 4-week period, an ocular irritation
rate of 0.04% was reported.77
A total of 7 participants were exposed (inhalation) to Shell Sol
TD at a concentration of 100 ppm for 5 days (6 h/d). The mean
concentration in the fat was 41.1 mg/kg (measured value), and Skin Irritation
the estimated mean half-life in fat was 7 days. At steady state,
C10-11 isoparaffin (Isopar G);
the maximum brain isoparaffin concentration was estimated to
C11-13 isoparaffin (Isopar L);
be 11 mg/kg, with an estimated maximum half-life of 18 to 19
C12-15 isoparaffin (Isopar M).
hours.71 Following exposure of 8 participants to Shell Sol TD
at a concentration of 100 ppm (0.6 g/m3) for 3 hours, the Under closed or semiocclusive conditions where evaporation
maximum steady-state concentration was calculated (using cannot freely occur, C10-11, C11-13, and C12-15 isoparaffins
mathematical modeling) to be 55 mg/kg for fat and 5 mg/kg can produce defatting of the skin and irritation.6
for the brain.72
C11-12 isoparaffin. The skin irritation potential of a hair
C8-12 Isoparaffin (Shell Sol TS) shine containing 41.25% C11-12 isoparaffin (as supplied) was
evaluated using 20 participants. The test substance was applied
None of the following symptoms associated with solvent expo- (3 repeated applications) under a semiocclusive patch for 24
sure was observed in 12 human participants, following a single, hours. The application area was not stated. It was concluded
6 hours of inhalation exposure to 100 ppm Shell Sol TS: head- that the product had very good skin compatibility. Whether or
ache, dizziness, feeling of inebriation, visual disturbances, not the hair shine product caused skin irritation was not stated
tremor, muscular weakness, impairment of coordination, or in the English translation (summary) of this study.78
paresthesia. A mean blood concentration of 2.3 mg/L (14
nmol/L) was reported at the end of exposure. There were no Isododecane. Results were negative for isododecane (con-
changes in blood chemistry, and results of urinalyses indicated tained *85% 2,2,4,6,6-pentamethylheptane) in an open patch
that exposure had no effect on the 2 urine variables albumin test involving 20 participants. However, skin irritation was
and b2-microglobulin.73 observed in a study in which 20 participants were patch tested
A total of 7 participants were exposed (inhalation) to Shell (closed patches) with the following concentrations of isodode-
Sol TS at a concentration of 103 ppm (0.61 g/m3) for 5 days cane (contains >98% 2,2,4,6,6-pentamethylheptane) in
288S International Journal of Toxicology 31(Supplement 3)

petrolatum: 10% (2 participants), 20% (3 participants), and phase and 65 participants completed the challenge phase.
50% (6 participants). A mixture containing 40% isododecane Safety was determined by evaluating dryness, redness, and
and 60% trimethylsiloxysilicate caused skin irritation in 2 of 19 stinging of the scalp and challenge phase data. The product
participants patch tested (closed patches) at a concentration of was classified as having very good tolerance, that is, no clini-
40% in petrolatum (effective isododecane concentration cally meaningful changes in redness and dryness on the scalp.
*16%).79 The skin reactivity observed during the challenge procedure
was considered as neither evidence of allergenicity nor clini-
Isohexadecane. The in-use safety of a tan-enhancing spray cally meaningful irritation.82
containing 42% isohexadecane, following 2 consecutive weeks The skin irritation and sensitization potential of a lip pri-
of use (once daily), was evaluated using 30 volunteers (males mer containing 80.74% isododecane was evaluated using
and females). Safety was determined by clinically evaluating 108 healthy male and female participants. The lip primer did
changes in dermatological data (dryness and redness) and not demonstrate a potential for eliciting skin irritation or
changes in opthalmological data (eg, eyelids and margins, con- sensitization. 83 Results for an eye shadow containing
junctivae, and corneas). Product-related adverse reactions 47.64% isododecane were also negative for skin irritation and
(4 participants total) included mild itching of forehead (1 parti- sensitization in a study involving 104 healthy male and female
cipant), burning sensation in left eye (1 participant), mild tin- participants,84 and the same was true for an eyeliner contain-
gling and itching of arms, chest, shoulders, and face ing 40.16% isododecane that was tested (2 cm  2 cm patch)
(1 participant), and mild tingling of cheeks. The changes on 108 participants during induction and 100 participants
observed in participants tested were reported to be not from the same group during the challenge phase.85 In another
clinically significant.80 study, the skin irritation and sensitization potential of a mas-
In a chemical safety report that was prepared in accordance cara containing 63.7% isododecane was evaluated using
with the REACH regulation, the results of a skin irritation test 204 healthy participants (males and females; 2 cm  2 cm
on isohexadecane involving 15 volunteers were negative.58 patches). It was concluded that the mascara was nonirritant
This finding is consistent with the results of skin irritation tests and nonsensitizer.86
on other isoparaffins included in this section. Patch applications of permethyl 296C (50% isododecane;
100  100 patches) were made to 52 healthy male and female
Isoeicosane. In a chemical safety report that was prepared in
participants. Results were not indicative of skin irritation or
accordance with the REACH regulation, the results of a skin
sensitization potential.87 In another study, permethyl 284C
irritation test on isoeicosane involving 15 volunteers were neg-
(20% isododecane; 100  100 patches) was applied to 52 healthy
ative.59 This finding is consistent with the results of skin irrita-
male and female participants. Two participants had a moderate
tion tests on other isoparaffins included in this section.
and barely perceptible reaction postchallenge. The barely per-
ceptible reaction was considered clinically insignificant and the
Predictive Skin Irritation and Sensitization moderate reaction was associated with a reactive participant
who should be prohibited from future patch testing. Results for
In most of the studies summarized in this section, an RIPT
permethyl 284C were not indicative of skin irritation or sensi-
procedure involving 24-hour patch applications (induction and
tization potential.88
challenge phases) to the back was used. The single application
In a chemical safety report that was prepared in accordance
procedure in the in-use safety test also involved a 24-hour
with the REACH regulation, data on hydrocarbons, C10-C12,
application period (challenge site not stated). If provided, the
iasoalkanes, and <2% aromatics were among the data used to
amount of test material applied is expressed in grams or milli-
evaluate the skin irritation and sensitization potential of isodo-
liters, and, in most cases, patch dimensions (in inches or cen-
decane in human participants.37 Results were positive for skin
timeters) are included.
irritation and negative for skin sensitization.
C11-12 isoparaffin. A mascara containing 48.28% C11-12
isoparaffin was applied (0.2 g under 2 cm  2 cm semiocclusive Isohexadecane. The skin irritation and sensitization potential
patches) to a total of 107 male and female participants. Transient of permethyl 216C (40% isohexadecane; 0.1 mL on 100  100
erythema and edema (slight reactions) were observed in 1 parti- patch) was evaluated using 52 healthy male and female parti-
cipant during induction, and the product was classified as a cipants, and results were negative.89 There was also no evi-
nonirritant (mean irritation index <0.25) and nonsensitizer.81 dence for skin irritation or sensitization in 100 male and
female participants tested with an indoor tanning product con-
Isododecane. The in-use safety of a hair oil mist spray con- taining 42% isohexadecane (0.1 mL/patch)90 or in 102 healthy
taining 90.3% isododecane, following 6 consecutive weeks of male and female participants tested with an eye makeup
use, was evaluated using 69 volunteers (males and females). remover containing 20% isohexadecane according to the same
The ability of the product to induce contact allergy was deter- procedure.91 In another study, a skin cleanser containing 15%
mined by conducting a challenge procedure (2 cm  2 cm site) isohexadecane (under 48 hour patch [0.5 in2]) did not induce
approximately 10 to 14 days after the use of the product was skin irritation, skin fatiguing, or allergic eczematous contact
discontinued. A total of 69 participants completed the in-use dermatitis in 600 healthy male and female participants.92
Jr et al 289S

In a chemical safety report that was prepared in accordance Isododecane. In a chemical safety report that was prepared
with the REACH regulation, human skin sensitization test data in accordance with the REACH regulation, data on hydrocar-
on hydrocarbons, C14-C18, n-alkanes, isoalkanes, cyclic, and bons, C10-C12, iasoalkanes, and <2% aromatics were among the
<2% aromatics were among the data used to evaluate the skin data used to evaluate the skin irritation and phototoxicity
sensitization potential of isohexadecane, and results were potential of isododecane in human participants, and results
negative.58 were negative.37
Isohexadecane and isoeicosane. Similarly, in chemical
Isododecane and isohexadecane. The skin irritation and sensi- safety reports that were prepared in accordance with the
tization potential of 20% EXP SR5 (contains 55.5% isohexa- REACH regulation, data on hydrocarbons, C14-C19, iasoalk-
decane and 35% isododecane; 0.2 g on 100  100 patch) in anes, cyclic, and <2% aromatics were among the data used to
petrolatum was evaluated using 54 healthy male and female evaluate the skin irritation and phototoxicity potential of iso-
participants. The effective concentrations tested were *11.1% hexadecane and isoeicosane in human participants, and the
isohexadecane and *7% isododecane. Neither skin irritation results were negative.58,59
nor sensitization was observed.93

Isoeicosane. Patch applications of permethyl 222C (40% iso- Case Report

eicosane; 100  100 patches) were made to 52 healthy male and
Isohexadecane. A 64-year-old female presented with a his-
female participants. Results were not indicative of skin irrita-
tory of an eczematous rash after application of a commercially
tion or sensitization potential.94 The same conclusion was
available sunscreen that contained isohexadecane. Patch test
stated in another study in which 106 healthy male and female
reactions to 10% isohexadecane were positive (þ reaction) at
participants were tested with a lip balm containing 27.15%
days 2 and 4. Negative results were reported for 20 control
isoeicosane.95
participants patch tested with isohexadecane.97
In a chemical safety report that was prepared in accordance
with the REACH regulation, data on hydrocarbons, C14-C18,
n-alkanes, isoalkanes, cyclic, and <2% aromatics were among Occupational Exposure
the data used to evaluate the skin sensitization potential of
The use of solvent mixtures containing isoparaffins in the
isoeicosane in human participants, and results were negative.59
workplace has produced a low incidence of
hypersensitization.6
Provocative Skin Sensitization Reportedly, C10-11 and C11-13 isoparaffins have been used
Isohexadecane. The skin sensitization potential of isohexade- by Versatec (a Xerox company) and Xerox Medical Systems,
cane was evaluated using a classical repetitive open application collectively, for over 16 years. Out of more than 2000 employ-
patch test. Patch applications were made to the outer upper arm ees, there were only 2 cases of health-related incidents (skin
of participants with dermatitis and to the anterior forearm and rash and hives) following skin contact.6
upper back of healthy participants (controls).96 Patch test Of the 74 male employees of a manufacturing facility, 63
reactions to isohexadecane (undiluted) were positive in 2 of developed dermatitis after exposure to the following 2 metal-
26 dermatitis patients and in 11 of 55 control participants; working fluids: lubricant containing >80% C9-12 isoparaffin
however, the difference between these 2 groups was not (lubricant 1) or >99.8% C10-14 isoparaffin (lubricant 2).98
statistically significant (P > .05). Isohexadecane (10% in Irritation test (procedure not stated) results indicated that
petrolatum) did not induce positive reactions in 19 dermatitis 22 of the 63 cases were due to lubricant 1 (PII ¼ 2.1) and 32
patients or in 56 control participants. The authors stated that, were due to lubricant 2 (PII ¼ 1.1); both were classified as
compared to control participants, the pattern of reactivity of irritants. Neither cumulative irritation nor sensitization tests
isohexadecane in participants with dermatitis suggested that it were performed.
acts unspecifically as an irritant when undiluted. The American Conference of Governmental Industrial
Hygienists set the occupational exposure limit for inhaled iso-
octane at 300 ppm, as time-weighted average.99
Skin Sensitization, Irritation, and Photosensitization
C10-11 isoparaffin (Isopar G) Epidemiology
C11-13 isoparaffin (Isopar L)
C12-15 isoparaffin (Isopar M) Aliphatic and other hydrocarbons. A study was designed to
provide an estimate of the occupational risk of contracting
Skin sensitization, phototoxicity, and photosensitization tests cancers of the urinary tract.100 The 25-year incidence of blad-
on Isopar G, Isopar L, and Isopar M were conducted using der cancer (BC) and renal cell carcinoma (RCC) in the entire
panels consisting of more than 100 participants. Each test mate- Finnish workforce was compared in relation to occupation and
rial was patch tested (semiocclusive patches) at a concentration occupational exposure to solvents and gasoline. The study
of 50% in petrolatum, and there was no evidence of skin sen- cohort consisted of 1.6 million Finns (born in years 1906-
sitization, phototoxicity, or photosensitization.6 1945) who participated in the national population census on
290S International Journal of Toxicology 31(Supplement 3)

December 31, 1970. All cancers, diagnosed from 1971 through metabolite, compared to males. Following human inhalation
1995, in individuals born in years 1906 to 1945 were extracted exposure, the maximum steady-state concentration of isooc-
from the nationwide Finnish Cancer Registry and sent to Sta- tane in the brain and fat was calculated using mathematical
tistics Finland and compared with the 1970 census files. Cancer modeling.
risk estimates were adjusted for smoking and obesity. Following exposure of 8 participants to Shell Sol TD at a
Overall, there appeared to be a tendency for an elevated risk concentration of 100 ppm (0.6 g/m3) for 3 hours, the maxi-
of BC in women exposed to solvents, but not among men. The mum steady-state concentration was calculated (using math-
relative risk estimates were above 1.2 in nearly all exposure ematical modeling) to be 55 mg/kg for fat and 5 mg/kg for the
categories studied. However, a statistically significant elevated brain.
risk of BC in women was associated with the following: a low Following lifetime dermal application of petrolatum (15% in
level of aliphatic hydrocarbon solvents (1.40; 95% confidence isooctane) to mice, no significant tumor incidence was found. A
interval (CI) ¼ 0.85-2.32), a low level of chlorinated hydro- 2007 toxicological review on 2,2,4-trimethylpentane (isooc-
carbon solvents (1.43; 95% CI ¼ 1.0-2.03), and a middle level tane), published by the EPA is available. The EPA has deter-
of chlorinated hydrocarbon solvents (1.68; 95% CI ¼ 1.15- mined that there is inadequate information to assess carcinogenic
2.45). The relative risks of BC in men and women occupation- potential of 2,2,4-trimethylpentane, having noted that no epide-
ally exposed to gasoline (low level exposure) were men 1.0 miological studies in humans and no chronic bioassay studies are
(95% CI ¼ 0.89-1.13) and women 1.55 (95% CI ¼ 0.50- available that assess the carcinogenic effects of 2,2,4-
4.86). There was no significantly elevated risk of RCC in any trimethylpentane.
exposure category for any solvent in either gender. It was con- In many of the animals studies, involving mostly male rats,
cluded that these findings suggest that occupational exposure to either oral or inhalation exposure to isooctane resulted in some
certain solvents may have an impact on BC risk, but the risk of degree of nephrotoxicity. According to some investigators,
RCC does not appear to be altered by exposure to hydrocarbon study results suggest that chronic cell proliferation associated
solvents or gasoline.100 with a2u-globulin nephropathy and chronic progressive nephro-
sis in male rats exposed to unleaded gasoline or its isoparaffinic
components, such as isooctane, may be responsible for nephro-
Summary carcinogenic effects of unleaded gasoline. a2u -Globulin
The 24 isoparaffins reviewed in this safety assessment function nephropathy associated with exposure to these chemicals is not
mostly as solvents in cosmetics, and the following 15 are being relevant to man due to the absence of this protein. The isopar-
used: C7-8 isoparaffin, C8-9 isoparaffin, C9-11 isoparaffin, affins were not found to be genotoxic in in vitro or in vivo
C10-11 isoparaffin, C10-13 isoparaffin, C11-12 isoparaffin, assays and were neither embryotoxic/fetotoxic nor teratogenic
C11-13 isoparaffin, C12-14 isoparaffin, C13-14 isoparaffin, in rats. The results of an initiation-promotion study involving
C13-16 isoparaffin, C18-70 isoparaffin, isododecane, isoeico- rats were negative for isooctane.
sane, isohexadecane, and isooctane. The results of a personal The isoparaffins have produced slight ocular irritation and
care products industry survey indicate that ingredient use con- mild-to-severe skin irritation but were not comedogenic, in
centrations have ranged from 0.0001% (C13-14 isoparaffin) to rabbits. Furthermore, skin sensitization was not induced in gui-
90% (isododecane). nea pigs. Eye area cosmetic products containing isoparaffins
As a frame of reference, liquid gasoline is a complex mix- were classified as well tolerated, in terms of ocular irritation
ture of petroleum chemicals that includes approximately 60% potential, following application to the eye lashes of female
to 75% alkanes (paraffins) that comprise straight-chain hydro- participants. Also, these chemicals, alone or in product formu-
carbons (C4-C12), and isoparaffins (branched-chain hydrocar- lations, were not classified as irritants, sensitizers, phototoxic,
bons) in approximately the same range of chain lengths. While or photosensitizers in human patch tests. However, it should be
some of the isoparaffins described as cosmetic ingredients are noted that isohexadecane (undiluted) induced a low incidence
longer in chain length, most are in this range. 2,2,4- of skin irritation in patients, but this incidence was not signif-
Trimethylpentane (isooctane) is used primarily in the alkyla- icantly different from that of healthy controls. Isohexadecane
tion step to derive high-octane gasoline fuels. (10% in petrolatum) did not induce any reactions in patients or
Following inhalation in rats, 14C-isooctane was eliminated healthy controls. Also, a low incidence of skin irritation was
almost exclusively by the kidneys, and various urinary meta- reported in a closed patch test, but results were negative in an
bolites, 2,4,4-trimethyl-2-pentanol included, have been iden- open patch test involving human participants tested with
tified. Following oral dosing of 14C-isooctane in rats, more isododecane.
than half of the administered dose was recovered in the urine Occupational exposure to isoparaffins has produced irrita-
and feces. Accumulation in the liver and kidneys was tion and a low incidence of sensitization in the workplace. In an
observed, with males retaining substantially greater amounts epidemiology study (occupational exposure), a statistically sig-
of radioactivity in the kidneys, compared to females. 2,4,4- nificant elevated risk of BC in women was associated with a
Trimethyl-2-pentanol was the major metabolite detected in low level of exposure to aliphatic hydrocarbon solvents. How-
the male rat kidney but was absent from female rat kidney. ever, a significantly elevated risk of RCC was not associated
However, female rats excreted more conjugates of this with these exposures.
Jr et al 291S

Discussion IIC. There was no evidence that Stoddard solvent IIC increased
tumor rates in female rats or male mice. The Expert Panel noted
The CIR Expert Panel noted that most of the available data
that male F344/N rats are uniquely susceptible to the develop-
related to oral or inhalation exposure to isoparaffins, but the
ment of adrenal medulla neoplasms under experimental condi-
dermal and ocular exposure data that were available, suggested
tions. These neoplasms are commonly observed in rats, both
mild ocular irritation, mild-to-severe irritation, no sensitization
unexposed and exposed to numerous, diverse, usually nonmu-
or photosensitization, and no phototoxicity.
tagenic chemicals in animal studies, but rarely in humans.
No significant toxicity was identified in oral or inhalation
Currently, there is no indication that substances inducing
exposure studies of the following end points: genotoxicity,
adrenal medulla neoplasms in animal experiments can induce
reproductive and developmental toxicity, or carcinogenicity.
these tumors in humans. Thus, the findings are generally
Nephrotoxicity, however, was a concern. The Expert Panel
considered not relevant to a human safety assessment.
noted the involvement of a2u-globulin in the mechanism for
Similarly, it was agreed that the liver tumors observed in
isoparaffin-induced nephrotoxicity/renal tubule cell prolifera-
B6C3F1 female mice are not relevant, because this strain of
tion in male rats of various strains in oral and inhalation expo-
mice is uniquely susceptible to hepatocellular adenomas, which
sure studies, but noted that nephrotoxic effects were not
are common in this strain.
observed in one strain of rats, NCI-Black-Reiter, that does not
The potential adverse effects of inhaled aerosols depend on
have the a2u-globulin protein. Humans also lack this protein
the specific chemical species, the concentration and the dura-
and, thus, the Panel agreed that findings associated with the
tion of the exposure and their site of deposition within the
a2u-globulin protein in male rats were not relevant to humans.
respiratory system. In practice, aerosols should have at least
This view was consistent with the US EPA position that it was
99% of their particle diameters in the 10 to 110 mm range and
not possible for the agency to derive an oral RfD for chronic
the mean particle diameter in a typical aerosol spray has been
oral exposure or a reference concentration for chronic inhala-
reported as *38 mm. Particles with an aerodynamic diameter
tion exposure to isooctane because the available studies were
of 10 mm are respirable. After reviewing the positive acute
limited, in that they were designed to only investigate the end
and subchronic inhalation toxicity data considered in this safety
points specific to a2u-globulin-associated nephropathy. The
assessment, the Expert Panel determined that isoparaffins can
EPA also concluded that there was inadequate evidence to
be used safely in hair sprays, because the product particle size
assess the carcinogenic potential of isooctane, based on the
is not respirable.
absence of human epidemiological studies and chronic bioas-
says on this compound. However, the CIR Expert Panel noted
that no significant tumor incidence was found following life- Conclusion
time dermal application of petrolatum (15% in isooctane) to The CIR Expert Panel concluded that the following ingredients
mice and also found no evidence of any concern regarding are safe in the present practices of use and concentration
carcinogenic potential from exposure to isoparaffins as used described in this safety assessment:
in cosmetics.
The Expert Panel also reviewed data in chemical safety  C7-8 isoparaffin;
reports on isooctane, isohexadecane, isododecane, and isoeico-  C8-9 isoparaffin;
sane that were submitted in accordance with the REACH reg-  C9-11 isoparaffin;
ulation. Very minimal data on either chemical are included in  C9-12 isoparaffin*;
these reports, and the majority of the data are on chemical  C9-13 isoparaffin*;
mixtures, comprising n-alkanes, isoalkanes, and aromatic com-  C9-14 isoparaffin*;
pounds that were used to evaluate the safety of the 4 isopar-  C9-16 isoparaffin*;
affins. Except for Stoddard solvent IIC (CAS No. 64742-88-7),  C10-11 isoparaffin;
these mixtures were not identified by common names or CAS  C10-12 isoparaffin*;
numbers in the safety reports, and percentage composition data  C10-13 isoparaffin;
were not included for any of the mixtures evaluated. Therefore,  C11-12 isoparaffin;
the Expert Panel did not agree that data on these mixtures  C11-13 isoparaffin;
should be used to evaluate the safety of isoparaffins in this  C11-14 isoparaffin*;
safety assessment, even though, except for the NTP carcino-  C12-14 isoparaffin;
genicity data on Stoddard solvent IIC, most of the data would  C12-20 isoparaffin*;
not raise any safety concerns and the findings are consistent  C13-14 isoparaffin;
with the results of similar studies on isoparaffins that support a  C13-16 isoparaffin;
safe conclusion for these ingredients in cosmetic products.  C18-70 isoparaffin;
The NTP concluded that inhalation exposure to Stoddard  C20-40 isoparaffin*;
solvent IIC caused cancer of the adrenal gland in male F344/  C15-35 isoparaffin/isoalkylcycloalkanes*;
N rats, and that an increase in liver tumors in female B6C3F1  Isooctane;
mice may have been related to exposure to Stoddard solvent  Isohexadecane;
292S International Journal of Toxicology 31(Supplement 3)

 Isododecane; hydrocarbon nephropathy (interim report) with cover letter dated

 Isoeicosane. 112685. NTIS Report No. OTS0000464-0. 1985.
13. Technical Committee on New and Existing Chemicals (TCNES)
Asterick (*) indicates the ingredients are not in current use. Subgroup on identification of persistent, bioaccumulative and toxic
Were these ingredients to be used in the future, the expectation PBT and very persistent and very bioaccumulative VPVB sub-
is that they would be used in product categories and at concen- stances. Results of the evaluation of the PBT/VPVB properties of
trations comparable to others in the group. alkanes, C9-12-iso-. http://ecb.jrc.ec.europa.eu/DOCUMENTS/
PBT_EVALUATION/PBT_sum024_CAS_90622-57.4.pdf.2008.
Authors’ Note 14. Mckee RH, Rohde AM, Daughtrey WC. Benzene levels in hydro-
Unpublished sources cited in this report are available from the Direc- carbon solvents—response to author’s reply. J Occup Environ
tor, Cosmetic Ingredient Review, 1101 17th St, Suite 412, Washing- Hyg. 2007;4(6):D60-D62.
ton, DC 20036, USA. 15. Food and Drug Administration. Synthetic isoparaffinic petroleum
hydrocarbons. 21 CFR 172.882. 2009.
Declaration of Conflicting Interests 16. Food and Drug Administration. Isoparaffinic petroleum hydrocar-
The author(s) declared no potential conflicts of interest with respect to bons, synthetic. 21 CFR 178.3530. 2009.
the research, authorship, and/or publication of this article. 17. Food and Drug Administration. Odorless light petroleum hydro-
carbons. 21 CFR 172.884. 2009.
Funding 18. Food and Drug Administration. Odorless light petroleum hydro-
The author(s) disclosed receipt of the following financial support for carbons. 21 CFR 178.3650. 2009.
the research, authorship, and/or publication of this article: The articles 19. Vieira PA, Vieira RB, Faria S, Ribeiro EJ, Cardoso VL.
in this supplement were sponsored by the Cosmetic Ingredient Biodegradation of diesel oil and gasoline contaminated efflu-
Review. The Cosmetic Ingredient Review is financially supported ent employing intermittent aeration. J Hazard Mater. 2009;
by the Personal Care Products Council. 168(2-3):1366-1372.
20. Gottschalck TE, Bailey JE. International Cosmetic Ingredient
References Dictionary and Handbook. Washington, DC: Personal Care Prod-
1. Elder RL. Final report on the safety assessment of fossil and ucts Council; 2010.
synthetic waxes. J Am Coll Toxicol. 1984;3:43-99. 21. Food and Drug Administration (FDA). Information Supplied to
2. Elder RL. Final report on the safety assessment of isobutane, FDA by Industry as Part of the VCRP FDA Database. Washing-
isopentane, n-butane, and propane. J Am Coll Toxicol. 1982; ton, DC: FDA; 2010.
1:127-142. 22. Personal Care Products Council. Use concentration data from
3. Andersen FA. Annual review of cosmetic ingredient safety industry survey. Unpublished data submitted by the Personal Care
assessments—2002/2003. Int J Toxicol. 2005;24(suppl 1):52-55. Products Council on July 8, 2010. 2010;1-5.
4. Andersen FA. Annual review of cosmetic ingredient safety 23. Personal Care Products Council. Concentration of use—C15-35
assessments—2002/2003. Int J Toxicol. 2005;24:67-74. isoparaffin/isoalkylcycloalkanes. 2010;1.
5. National Library of Medicine. Hazardous Substances Data Bank. 24. James AC, Stahlhofen W, Rudolf G, et al. Deposition of inhaled
2010. http://www.nlm.nih.gov/ particles. Ann ICRP. 1994;24:231-232.
6. Mullin LS, Ader AW, Daughtrey WC, Frost DZ, Greenwood MR. 25. Obersorster G, Oberdorster E, Oberdorster J. Nanotoxicology: an
Toxicology update: isoparaffinic hydrocarbons: a summary of emerging discipline evolving from studies of ultrafine particles.
physical properties, toxicity studies and human exposure data. Environ Health Perspect. 2005;113(7):823-839.
J Appl Toxicol. 1990;10(2):135-142. 26. Bower D. Unpublished information on hair spray particle sizes
7. MB Research Labs. Eight toxicity reports on 2,2,4-trimethyl provided at the September 9, 1999 CIR Expert Panel meeting. 1999.
pentane (isooctane) with attachments and cover letter dated 27. Johnson MA. The influence of particle size. Spray Technol Mar-
072987. NTIS Report No. OTS0515208. 1978;1-660. ket. 2004;24-27.
8. Chevron Phillips Chemical Company LP. Material Safety Data 28. Balster RL, Bowen SE, Evans EB, Tokarz ME. Evaluation of the
Sheet. Isooctane (pure grade). 2009. acute behavioral effects and abuse potential of a C8-C9 isopar-
9. Howe-Grant M. Kirk-Othmer Concise Encyclopedia of Chemi- affin solvent. Drug Alcohol Depend. 1997;46(3):125-135.
cal Technology. 4th ed. New York, NY: Wiley-Interscience; 29. Mehlman MA. Dangerous and cancer-causing properties of prod-
2001:982-982. ucts and chemicals in the oil refining and petrochemical industry:
10. Ineos. Isoparaffin cosmetics review comments.doc. Isoparaffin Part I. Carcinogenicity of motor fuels: gasoline. Toxicol Ind
references.doc. Unpublished data submitted by Ineos on August Health. 1991;7(5-6):143-152.
27, 2010. 2010;1-48. 30. Zhang HR, Eddings EG, Sarofim AF. Pollutant emissions from
11. Ineos. Ineos Oligomers—General product information. Isodode- gasoline combustion. 1. Dependence on fuel structural function-
cane in the production of LDPE. Unpublished data submitted by alities. Environ Sci Technol. 2008;42(15):5615-5621.
Ineos on August 27, 2010. 2006;1-6. 31. The United States Pharmacopeial Convention. The United States
12. American Petroleum Institute (API). Investigation of the altera- Pharmacopeia. The National Formulary. USP 32-USP 32. Rock-
tions in renal function in animals during induction of light ville, MD: The United States Pharmacopeial Convention; 2009.
Jr et al 293S

32. Dahl AR. The fate of inhaled octane and the nephrotoxicant, 50. Dietrich DR, Swenberg A. NCI-Black-Reiter (NBR) male rats fail
isooctane, in rats. Toxicol Appl Pharmacol. 1989;100(2):334-341. to develop renal disease following exposure to agents that induce
33. Olson CT, Yu KO, Hobson DW, Serve MP. Identification of alpha2U-globulin (alpha2U) nephropathy. Fundam Appl Toxicol.
urinary metabolites of the nephrotoxic hydrocarbon 2,2,4- 1991;16(4):749-762.
trimethylpentane in male rats. Biochem Biophys Res Commun. 51. INEOS Manufacturing Deutschland GmbH. Chemical safety
1985;130(1):313-316. report. 2,2,4-trimethylpentane. 2010;1-202.
34. Lock EA, Charbonneau M, Strasser J, Wenberg JA, Bus JS. 2,2,4- 52. BioScience Laboratories, Inc. In vitro evaluation of various
trimethylpentane-induced nephrotoxicity. II. The reversible bind- test products for ocular irritation using the MTT ET-50 reduc-
ing of a TMP metabolite to a renal protein fraction containing alpha tion method (tan enhancing spray contains 42% isohexade-
2 microglobulin. Toxicol Appl Pharmacol. 1987;91(2):182-192. cane). Study Number 070217-2070. Unpublished data
35. Kloss MW, Swenberg J, Bus JS. Sex-dependent differences in submitted by the Personal Care Products Council on August
disposition of [14C-5]-2,2,4-trimethylpentane in Fischer 344 rats 31, 2010. 2007;1-62.
with cover sheet. NTIS Report No. OTS0516167. 1987;1-8. 53. Consumer Product Testing Co. The hen’s egg test—utilizing the
36. Charbonneau M, Lock EA, Strasser J, Cox MG, Turner MJ, Bus chorioallantoic membrane (HET-CAM). Exp. SR-5 Lot # 083007.
JS. 2,2,4-Trimethylpentane-induced nephrotoxicity. I. Metabolic Unpublished data submitted by Presperse, LLC on August 2010.
disposition of TMP in male and female Fischer 344 rats. Toxicol 2007;1-6.
Appl Pharmacol. 1987;91(2):171-181. 54. Consumer Product Testing Co. The hen’s egg test—utilizing
37. INEOS Manufacturing Deutschland. Chemical safety report. Iso- the chorioallantoic membrane (HET-CAM). Permethyl 216C
dodecane. 2010;1-464. Lot # 061708. Unpublished data submitted by Prespers, LLC
38. European Commission—European Chemicals Bureau.IUCLID on August 2010. 2006;1-6.
Dataset. 2,2,4-trimethylpentane. 2000. 55. Consumer Product Testing Co. The hen’s egg test—utilizing
39. Phillips RD, Egan GF. Effects of C10-C11 isoparaffinic solvent the chorioallantoic membrane (HET-CAM). Permethyl 284C
on kidney function in Fischer 344 rats during eight weeks of Lot # 062809. Unpublished data submitted by Presperse, LLC
inhalation. Toxicol Appl Pharmacol. 1984;73(3):500-510. on August 2010. 2006;1-6.
40. Phillips RD, Cockrell BY. Kidney structural changes in rats fol- 56. Consumer Product Testing Co. The hen’s egg test—utilizing
lowing inhalation exposure to C10-C11 isoparaffinic solvent. the chorioallantoic membrane (HET-CAM). Permethyl 296C
Toxicology. 1984;33(3-4):261-273. Lot # 062609. Unpublished data submitted by Presperse, LLC
41. Schreiner C, Lapadula E, Breglia R, et al. Toxicity evaluation of on August 2010. 2006;1-6.
petroleum blending streams: inhalation subchronic toxicity/neu- 57. Consumer Product Testing Co. The hen’s eff test—utilizing
rotoxicity study of a light alkylate naphtha distillate in rats. the chorioallantoic membrane (HET-CAM). Permethyl 222C
J Toxicol Environ Health A. 1998;55(4):277-296. Lot # 061209. Unpublished data submitted by Presperse, LLC
42. Phillips RD, Egan GF. Subchronic inhalation exposure of dear- on August 2010. 2006;1-6.
omatized white spirit and C10-C11 isoparaffinic hydrocarbon in 58. INEOS Manufacturing Deutschland GmbH. Chemical safety
sprague-dawley rats. Fundam Appl Toxicol. 1984;4(5):808-818. report. Isohexadecane. 2010;1-187.
43. CIVO Inst TNO, Netherlands. Initial submission: Subchronic 59. INEOS Manufacturing Deutschland GmbH. Chemical safety
(13-week) inhalation toxicity study with isododecane in rats, report. Isoeicosane. 2006;1-125.
with TSCA hlth & sfty study cvr sht dated 120899. NTIS Report 60. Product Safety Labs. Comedogenicity assay. Permethyl 99AD.
No. OTS0559857. 1999;1-10. Unpublished data submitted by Presperse, LLD on August
44. U.S. Environmental Protection Agency (EPA). Integrated Risk 2010. 1989;1-9.
Information System. Status of data for 2,2,4-trimethylpentane. 61. Product Safety Labs. Permethyl 99A (comedogenicity assay).
2007. Unpublished data submitted by Presperse, LLC on August
45. Short BG, Burnett VL, Swenberg JA. Histopathology and cell 2010. 1987;1-8.
proliferation induced by 2,2,4-trimethylpentane in the male rat 62. Product Safety Labs. Comedogenicity assay. Permethyl 101A.
kidney. Toxicol Pathol. 1986;14(2):194-203. Unpublished data submitted by Presperse, LLC on August
46. Fowlie AJ, Grasso P, Bridges JW. Renal and hepatic lesions induced 2010. 1986;1-5.
by 2,2,4-trimethylpentane. J Appl Toxicol. 1987;7(5):335-341. 63. Lijinsky W, Saffioti U, Shubik P. Evaluation of possible carcino-
47. Viau C, Bernard A, Gueret F, Maldague P, Gengoux P, Lauwerys genicity of petroleum products in therapeutic use. UICC Mono-
R. Isoparaffinic solvent-induced nephrotoxicity in the rat. Toxi- graph Series. 1967;7:129-135.
cology. 1986;38(2):227-240. 64. Short BG, Burnett VL, Swenberg JA. Elevated proliferation of
48. Swenberg JA, Short B, Borghoff S, Strasser J, Charbonneau M. proximal tubule cells and localization of accumulated
The comparative pathobiology of alpha 2u-globulin nephropathy. alpha2micro-globulin in F344 rats during chronic exposure to
Toxicol Appl Pharmacol. 1989;97(1):35-46. unleaded gasoline or 2,2,4-trimethylpentane. Toxicol Appl Phar-
49. Stonard MD, Phillips PG, Foster JR, Simpson MG, Lock EA. macol. 1989;101(3):414-431.
Alpha 2U-globulin: measurement in rat kidney following admin- 65. Short BG, Steinhagen WH, Swenberg JA. Promoting effects of
istration of 2,2,4-trimethylpentane. Toxicology. 1986;41(2): unleaded gasoline and 2,2,4-trimethylpentane on the development
161-168. of atypical cell foci and renal tubular cell tumors in rats exposed
294S International Journal of Toxicology 31(Supplement 3)

to N-ethyl-N-hydroxyethylnitrosamine. Cancer Res. 1989;49(22): isohexadecane). RCTS’ Study No. 2358. Unpublished data sub-
6369-6378. mitted by the Personal Care Products Council on August 31, 2010.
66. Richardson KA, Wilmer JL, Smith-Simpson D, Skopek TR. 2008;1-62.
Assessment of the genotoxic potential of unleaded gasoline and 81. Institut d’Expertise Clinique. Sensitization and cutaneous com-
2,2,4-trimethylpentane in human lymphoblasts in vitro. Toxicol patibility study of a mascara (6385887) containing 48.28% C11-
Appl Pharmacol. 1986;82(2):316-322. 12 isoparaffin. Report No. B061620RD5. Unpublished data sub-
67. McLaren J, Boulikas T, Vamvakas S. Induction of poly(ADP- mitted by the Personal Care Products Council on August 31, 2010.
ribosyl)ation in the kidney after in vivo application of renal car- 2007;1-64.
cinogens. Toxicology. 1994;88(1-3):101-112. 82. RCTS, Inc. Clinical evaluation of the safety-in-use of an hair oil
68. Loury DJ, Smith-Oliver T, Strom S, Jirtle R, Michalopoulos G, mist spray containing 90.3% isododecane. Unpublished data sub-
Butterworth BE. Assessment of unscheduled and replicative DNA mitted by the Personal Care Products Council on August 31, 2010.
synthesis in hepatocytes treated in vivo and in vitro with unleaded 2010;1-70.
gasoline or 2,2,4-trimethylpentane. Toxicol Appl Pharmacol. 83. Clinical Research Laboratories, Inc. Repeated insult patch test on
1986;85(1):11-23. a lip primer containing 80.74% isododecane. Contains: Permethyl
69. U.S. Environmental Protection Agency (EPA). Toxicological 99A. Unpublished data submitted by the Personal Care Products
review of 2,2,4-trimethylpentane (CAS No. 540-84-1). In support Council on August 23, 2010. 2004;1-13.
of summary information on the Integrated Risk Information 84. Clinical Reserach Laboratories, Inc. Repeated insult patch test of
System. 2007. an eye shadow containing 47.64% isododecane. Unpublished data
70. Forman S, Kas J, Fini F, Steinberg M, Ruml T. The effect of submitted by the Personal Care Products Council on August 23,
different solvents on the ATP/ADP content and growth properties 2010. 2006;1-13.
of HeLa cells. J Biochem Mol Toxicol. 1999;13(1):11-15. 85. Product Investigations, Inc. Determination of the irritating and
71. Pedersen LM, Larsen K, Cohr CH. Kinetics of white spirit in sensitizing propensities of an eyeliner containing 40.16% isodo-
human fat and blood during short term experimental exposure. decane on human skin. Unpublished data submitted by the Per-
Acta Pharmacol Toxicol (Copenh). 1984;55(4):308-316. sonal Care Products Council on August 23, 2010. 2005;1-11.
72. Pedersen LM, Rasmussen S, Cohr CH. Further evaluation of the 86. TKL Research. Human repeat insult patch test of formula no.
kinetics of white spirit in human volunteers. Pharmacol Toxicol. 637615 (mascara containing 63.7% isododecane). Study No.
1987;60(2):135-139. DS107703. Unpublished data submitted by the Personal Care
73. Pedersen LM, Cohr K. Biochemical pattern in exposure of Products Council on August 31, 2010. 2004;1-47.
humans to white spirit. I. The effects of a 6 h single dose. Acta 87. Consumer Product Testing Co. Repeated insult patch test protocol
Pharmacol Toxicol (Copenh). 1984;55(4):317-324. No.: 1.10. Permethyl 296C Lot# 062609. Unpublished data sub-
74. Pedersen LM, Cohr K. Biochemical pattern in exposure of mitted by Presperse, LLC on August 2010. 2006;1-9.
humans to white spirit II. Acta Pharmacol Toxicol (Copenh). 88. Consumer Product Testing Co. Repeated insult patch test protocol
1984;55(4):325-330. No.: 1.01. Permethyl 284C Lot# 062809. Unpublished data sub-
75. Dermexpert Int. Use test under ophthalmological control of a mitted by Presperse, LLC on August 2010. 2006;1-9.
mascara (6385887) containing 48.28% C11-12 isoparaffin. 89. Consumer Product Testing Co. Repeated insult patch test protocol
Unpublished data submitted by the Personal Care products Coun- No.: 101. Permethyl 216C Lot# 061708. Unpublished data sub-
cil on August 31, 2010. 2007;1-2. mitted by Presperse, LLC on August 2010. 2007;1-9.
76. Peritesco. Five-day tolerance study of a mascara containing 63. 90. TKL Research. Repeated insult patch test of an indoor tanning
7% isododecane. Report No. 2790-43-0. Unpublished data sub- product containing 42% isohexadecane. TKL Study No.
mitted by the Personal Care Products Council on August 31, 2010. DS108707-6. Unpublished data submitted by the Personal Care
2004;1-75. Products Council on August 31, 2010. 2008;1-62.
77. Peritesco. Four-week ocular tolerance study of a mascara contain- 91. Clinical Research Laboratories, Inc. Repeated insult patch test of
ing 63.7% isododecane. Report No. 2605-43-0. Unpublished data an eye makeup remover containing 20% isohexadecane. Unpub-
submitted by the Personal Care Products Council on August 31, lished data submitted by the Personal Care Products Council on
2010. 2005;1-62. August 23, 2010. 1998;1-14.
78. Institut d’Expertise Clinique. Summary of the results on 20 sub- 92. Orentreich Research Corporation. Predictive patch test study of a
jects after 3 repeated applications under semi-occlusive patch skin cleanser containing 15% isohexadecane. Unpublished data
for 24 hours (product no. 1078547 hair shine contains 41.25% submitted by the Personal Care Products Council on August 23,
C11-12 isoparaffin). REF: B090232FR. Unpublished data sub- 2010. 2005;1-27.
mitted by the Personal Care Products Council on August 31, 93. Consumer Product Testing Co. Repeated insult patch test protocol
2010. 2009;1-6. no.: 1.01. (20%) EXP-SR5 in petrolatum Lot# 112907. Unpub-
79. Personal Care Products Council. Summaries of studies on iso- lished data submitted by Presperse, LLC on August 2010. 2008;
dodecane. Unpublished data submitted by the Personal Care 1-9.
Products Council on September 9, 2010. 2010;1-2. 94. Consumer Product Testing Co. Repeated insult patch test protocol
80. Reliance Clinical Testing Services, Inc. Clinical evaluation of the no.: 1.01. Permethyl 222C Lot# 061209. Unpublished data sub-
safety-in-use of a tan enhancing spray (contains 42% mitted by Presperse, LLC on August 2010. 2006;1-9.
Jr et al 295S

95. Clinical Research Laboratories, Inc. Repeated insult patch test of 104. Laboratory for Pharmacology and toxicology (Hamburg). Study
a lip balm containing 27.15% isoeicosane. Contains Permethyl of the acute toxicity of Permethyl 101A, isohexadecane, on oral
102A. Unpublished data submitted by the Personal Care Products administration to rats. Unpublished data submitted by Presperse,
Council on August 23, 2010. 1996;1-14. LLC on August 2010. 1980;4-10.
96. Elsner P, Maibach HI. Papular and follicular contact dermatitis: 105. Product Safety Labs. FHSA primary eye irritation test. Per-
irritation and/or allergy. Curr Probl Dermatol. 1995;23:9-17. methyl 99 AD. Unpublished data submitted by Presperse, LLC
97. Bharati A, King CM. Allergic contact dermatitis from isohexade- on August 2010. 1989;1-9.
cane and isopropyl myristate. Contact Dermatitis. 2004;50(4): 106. Product Safety Labs. Permethyl 99A (FHSA primary eye irrita-
256-257. tion test). Unpublished data submitted by Presperse, LLC on
98. Ueno S, Shiomi Y, Yokota K. Metalworking fluid hand dermati- August 2010. 1987;1-9.
tis. Ind Health. 2002;40(3):291-293. 107. Laboratory for Pharmacology and toxicology (Hamburg). Muco-
99. ACGIH. TLVs1 and BEIs1 Based on the Documentation of the sal tolerance of Permethyl 101A, isohexadecane, in the rabbit
Threshold Limit Values for Chemical Substances and Physical eye after single application. Unpublished data submitted by Pre-
Agents and Biological Exposure Indices. Cincinnati, OH: Signa- sperse, LLC on August 2010. 1980;11-19.
ture Publications; 2010. 108. Product Safety Labs. FHSA dermal irritation test. Permethyl
100. Lohi J, Kyyronen P, Kauppinen T, Kujala V, Pukkala E. Occu- 99AD. Unpublished data submitted by Presperse, LLC on
pational exposure to solvents and gasoline and risk of cancers in August 2010. 1989;1-7.
the urinary tract among Finnish workers. Am J Ind Med. 2008; 109. Product Safety Labs. Permethyl 99A (FHSA dermal irritation
51(9):668-672. test). Unpublished data submitted by Presperse, LLC on August
101. Scientific and Technical Information Network (STN).Registry 2010. 1987;1-6.
file. 2010. 110. Laboratory for Pharmacology and toxicology (Hamburg). Study
102. Bowen SE, Balster RL. The effects of inhaled isoparaffins on on the local tolerance of Permethyl 101A, isohexadecane, on the
locomotor activity and operant performance in mice. Pharmacol rabbit skin (patch test). Unpublished data submitted by Pre-
Biochem Behav. 1998;61(3):271-280. sperse, LLC on August 2010. 1980;20-28.
103. Product Safety Labs. Permethyl 99A (FHSA acute oral limit 111. Microbiological Associates Inc. The L5178Y TKþ/- mouse
test). Unpublished data submitted by Presperse, LLC on August lymphoma assay. NTIS Report No. OTS0000560-0. 1987;
2010. 1987;1-6. 1-11.