International Journal of Toxicology, 24(Suppl.

5):53–100, 2005
Copyright c American College of Toxicology
ISSN: 1091-5818 print / 1092-874X online
DOI: 10.1080/10915810500434209

Final Report of the Safety Assessment of Methacrylate Ester

Monomers Used in Nail Enhancement Products1

guinea pig study, but was a strong sensitizer in another. There is

Methacrylate ester monomers are used in as artificial nail cross-reactivity between various methacrylate esters in some sensi-
builders in nail enhancement products. They undergo rapid poly- tization tests. Inhaled Butyl Methacrylate, HEMA, Hydroxypropyl
merization to form a hard material on the nail that is then shaped. Methacrylate, and Trimethylolpropane Trimethacrylate can be de-
While Ethyl Methacrylate is the primary monomer used in nail velopmental toxicants at high exposure levels (1000 mg/kg/day).
enhancement products, other methacrylate esters are also used. None of the methacrylate ester monomers that were tested were
This safety assessment addresses 22 other methacrylate esters re- shown to have any endocrine disrupting activity. These methacry-
ported by industry to be present in small percentages as artifi- late esters are mostly non-mutagenic in bacterial test systems, but
cial nail builders in cosmetic products. They function to speed weak mutagenic responses were seen in mammalian cell test sys-
up polymerization and/or form cross-links. Only Tetrahydrofur- tems. Chronic dermal exposure of mice to PEG-4 Dimethacry-
furyl Methacrylate was reported to the FDA to be in current late (25 mg, 2× weekly for 80 weeks) or Trimethylolpropane
use. The polymerization rates of these methacrylate esters are Trimethacrylate (25 mg, 2× weekly for 80 weeks) did not result in
within the same range as Ethyl Methacrylate. While data are increased incidence of skin or visceral tumors. The carcinogenic-
not available on all of these methacrylate esters, the available ity of Triethylene Glycol Dimethacrylate (5, 25, or 50%) was as-
data demonstrated little acute oral, dermal, or i.p. toxicity. In a sessed in a mouse skin painting study (50 μl for 5 days/week for 78
28-day inhalation study on rats, Butyl Methacrylate caused up- weeks), but was not carcinogenic at any dose level tested. The Ex-
per airway irritation; the NOAEL was 1801 mg/m3 . In a 28-day pert Panel was concerned about the strong sensitization and cross-
oral toxicity study on rats, t-Butyl Methacrylate had a NOAEL of or co-reactivity potential of the methacrylate esters reviewed in this
20 mg/kg/day. Beagle dogs dosed with 0.2 to 2.0 g/kg/day of C12 report. However, data demonstrated the rates of polymerization of
to C18 methacrylate monomers for 13 weeks exhibited effects only these Methacrylates were similar to that of Ethyl Methacrylate
in the highest dose group: weight loss, emesis, diarrhea, mucoid and there would be little monomer available exposure to the skin.
feces, or salivation were observed. Butyl Methacrylate (0.1 M) and In consideration of the animal toxicity data, the CIR Expert Panel
Isobutyl Methacrylate (0.1 M) are mildly irritating to the rabbit eye. decided that these methacrylate esters should be restricted to the
HEMA is corrosive when instilled in the rabbit eye, while PEG-4 nail and must not be in contact with the skin. Accordingly, these
Dimethacrylate and Trimethylolpropane Trimethacrylate are min- methacrylate esters are safe as used in nail enhancement products
imally irritating to the eye. Dermal irritation caused by methacry- when skin contact is avoided.
lates is documented in guinea pigs and rabbits. In guinea pigs,
HEMA , Isopropylidenediphenyl Bisglycidyl Methacrylate, Lauryl
Methacrylate, and Trimethylolpropane Trimethacrylate are strong
sensitizers; Butyl Methacrylate, Cyclohexyl Methacrylate, Hexyl INTRODUCTION
Methacrylate, and Urethane Methacrylate are moderate sensitiz- The Methacrylate Producers Association (MPA) initially ex-
ers; Hydroxypropyl Methacrylate is a weak sensitizer; and PEG-4 pressed concerns to the Cosmetic Ingredient Review (CIR)
Dimethacrylate and Triethylene Glycol Dimethacrylate are not sen-
sitizers. Ethylene Glycol Dimethacrylate was not a sensitizer in one
Expert Panel in 1998 regarding the safety of methacrylate
use in consumer products (Methacrylate Producers Associa-
tion 1998). The MPA argued that because of the sensitization
1
potential of methacrylate esters, these chemicals were inap-
This safety assessment includes Butyl Methacrylate, t-Butyl
Methacrylate, Cyclohexyl Methacrylate, Di-HEMA Trimethylhexyl
propriate for use in consumer products. In addition, the MPA
Dicarbamate, Ethoxyethyl Methacrylate, 2-Ethoxy Ethoxy Ethyl raised concerns about the use of Methacrylic Acid in consumer
Methacrylate, Ethylene Glycol Dimethacrylate, HEMA, HEMA Ace- products.
toacetate, Hexyl Methacrylate, Hydroxypropyl Methacrylate, Isobornyl To address these issues, the CIR Expert Panel agreed to
Methacrylate, Isobutyl Methacrylate, Isopropylidenediphenyl Bisoxy- undertake three new safety assessments on: (1) Methacrylic
hydroxypropyl Methacrylate, Lauryl Methacrylate, Methoxydigly-
col Methacrylate, PEG-4 Dimethacrylate, Pyromellitic Glycidyl
Acid; (2) Butyl Methacrylate, Isobutyl Methacrylate, and
Dimethacrylate, Tetrahydrofurfuryl Methacrylate, Triethylene Glycol Lauryl Methacrylate; and (3) Methyl Methacrylate. The safety
Dimethacrylate, Trimethylolpropane Trimethacrylate, and Urethane assessment of Methacrylic Acid was completed in September,
Methacrylate. 2001 (CIR 2001). The safety assessment of Methyl Methacry-
Reviewed by the Cosmetic Ingredient Review (CIR) Expert Panel. late was terminated in favor of a statement of support for the
This report was prepared by Alexander Escobar and Torill Ann Ya-
marik, former CIR staff. Address correspondence to F. Alan Andersen, FDA position against the use of Methyl Methacrylate in nail
Director, CIR, 1101 17th St., NW, Suite 310, Washington, DC 20036, enhancement products. This safety assessment addresses the
USA. Butyl Methacrylate group of methacrylate esters.

53
54 COSMETIC INGREDIENT REVIEW

In addition to the original list of Butyl, Isobutyl, and Lauryl methacrylate esters addressed in this safety assessment, there-
Methacrylate, the Nail Manufacturers Council (NMC) submitted fore, information from the 1999 CIR Final Report on the
a list of other Methacrylates used in nail enhancement products Safety Assessment of Ethyl Methacrylate is included. Similarly,
which were added to this report. chronic toxicity and carcinogenicity data on methyl methacry-
In this safety assessment, therefore, Butyl Methacrylate, late are incorporated in the report.
sec-Butyl Methacrylate, t-Butyl Methacrylate, Cyclohexyl
Methacrylate, Di-HEMA Trimethylhexyl Dicarbamate,
Ethoxyethyl Methacrylate, 2-Ethoxy Ethoxy Ethyl Methacry- CHEMISTRY
late, Ethylene Glycol Dimethacrylate, Hexyl Methacrylate, Definition and Structure
HEMA, HEMA Acetoacetate, Hydroxypropyl Methacrylate,
Figure 1 provides information on the structures of these
Isobornyl Methacrylate, Isobutyl Methacrylate, Isopropy-
methacrylate monomers. Table 1 presents the definition, syn-
lidenediphenyl Bisoxyhydroxypropyl Methacrylate, Lauryl
onyms, CAS number, etc. of each of the ingredients in this safety
Methacrylate, Methoxydiglycol Methacrylate, Pyromellitic
assessment. As noted earlier, a definition from the International
Glycidyl Dimethacrylate, PEG-4 Dimethacylate, Tetrahydro-
Cosmetic Ingredient Dictionary and Handbook is not available
furfuryl Methacrylate, Triethylene Glycol Dimethacrylate,
in all cases.
Trimethylolpropane Trimethacrylate, and Urethane Methacry-
late are being reviewed as artificial nail builders in cosmetic
products. PHYSICAL AND CHEMICAL PROPERTIES
Official cosmetic ingredient names have not been estab- The physical and chemical properties of Butyl, Isobutyl, and
lished for 2-Ethoxy Ethoxy Ethyl Methacrylate; Ethylene Gly- Lauryl Methacrylate are shown in Table 2. Although both Butyl
col Dimethacrylate; Hexyl Methacrylate; Pyromellitic Glycidyl Methacrylate and Lauryl Methacrylate were reported as insolu-
Dimethacrylate; Tetrahydrofurfuryl Methacrylate; and Urethane ble in water (see Table 1), Assessment Technologies, Inc., (1996)
Methacrylate. The American Beauty Association (ABA)/NMC cited their solubility in water as 134–141 mg/L and <0.10–
is working to add these methacrylates used in nail enhancing 19.0 mg/L, respectively.
products to the International Cosmetic Ingredient Dictionary
and Handbook (ABA/NMC 2001a).
Butyl Methacrylate, t-Butyl Methacrylate, Cyclohexyl Curing of Commercial Products
Methacrylate, Di-HEMA Trimethylhexyl Dicarbamate, In the CIR Final Report on the Safety Assessment of Ethyl
Ethoxyethyl Methacrylate, HEMA, HEMA Acetoacetate, Methacrylate, there were data submitted by Schoon (1994a;
Hydroxypropyl Methacrylate, Isobornyl Methacrylate, 1994b), on the extent of curing and the amount of unre-
Isobutyl Methacrylate, Isopropylidenediphenyl Bisoxyhydrox- acted monomer in two fingernail formulations containing ethyl
ypropyl Methacrylate, Lauryl Methacrylate, Methoxydiglycol methacrylate. The study established there was sufficient poly-
Methacrylate, PEG-4 Dimethacrylate, Triethylene Glycol merization of ethyl methacrylate in ethyl methacrylate nail en-
Dimethacrylate, and Trimethylolpropane Methacrylate are hancement systems, such that there are insignificant amounts of
listed in the International Cosmetic Ingredient Dictionary and monomers after 4 hours of curing.
Handbook (Gottschalck and McEwen 2004). A study submitted by Creative Nail Design (2001) analyzed
Ethyl methacrylate represents over 90% of the monomer used the polymerization of the 22 Methacrylates (see Table 3) in an
in nail enhancement products. An amended safety assessment ethyl methacrylate based system using Differential Scanning
of Ethyl Methacrylate was completed in 1999 (CIR 1999). Use Calorimetry (DSC) to measure the reactivity and set time of
of Ethyl Methacrylate in nail enhancement products became Methacrylate monomers. The reactivity of the methacrylate “test
widespread following action by the Food and Drug Adminis- monomers” in the model system was determined using DSC.
tration (FDA) to remove a product from the market containing Maximum peak exotherm and total exotherm were measured
Methyl Methacrylate. FDA obtained an injunction in 1974 to while the nail enhancement product reacted in the test cham-
prohibit the manufacture and interstate shipment of a product ber. Maximum peak exotherm occurs at gelation (gel point) of a
called “Long Nails” because of consumer complaints of se- curing nail enhancement system. The gelation point is reached
vere adverse reactions to Methyl Methacrylate monomer (Fisher when at least 50% of the monomer has reacted and the mate-
1990). rial has a hardened surface. This process take 2 to 4 minutes
In comparison to Ethyl Methacrylate, the methacrylate esters in most commercially available professional monomer based
reviewed in this report are secondary monomers used at much nail enhancement systems. Changes in gel point time and total
lower concentrations to speed up polymerization and act as cross exotherm are both directly proportional to the test monomers’
linkers formulation (ABA/NMC 2001a). reactivity.
Very little information has been identified in the published In the experiment, the RadicalTM artificial nail monomer/
literature regarding mammalian mutagenicity studies on the polymer system was modified by adding 5% ethyl methacrylate
ESTER MONOMERS USED IN NAIL ENHANCEMENT PRODUCTS 55

FIGURE 1
Structure of Methacrylate Esters
56 COSMETIC INGREDIENT REVIEW

FIGURE 1
(Continued)
ESTER MONOMERS USED IN NAIL ENHANCEMENT PRODUCTS 57

FIGURE 1
(Continued)
58 COSMETIC INGREDIENT REVIEW

FIGURE 1
(Continued).

to establish a normalized baseline to compare reactivity of var- acid and subsequent esterification in sulfuric acid with the
ious test monomers. Each of the 22 test monomers were added appropriate alcohol (HSDB 2001).
at a concentration of 5% (by weight) to the RadicalTM artificial
nail monomer/polymer system (see Table 3). The results re- Analytical Methods
ported most test monomers at 5% concentrations had faster Butyl, Hexyl, Isobutyl, and Lauryl Methacrylate were ana-
set times than the 5% ethyl methacrylate standard. At 3.84 lyzed by gas chromatography with a flame ionization detector
minutes, 5% Hexyl Methacrylate was the slowest to set, 0.74 (Horna et al. 1985).
minutes slower than the set time for 5% ethyl methacrylate. Henriks-Eckerman and Kanerva (1997) identified the pres-
At 285.83 mJ/m2 , t-Butyl Methacrylate had the lowest total ence of Butyl Methacrylate (0.05%) in an acrylic adhesive using
exotherm, which was 50.75 mJ/m2 lower than the total exotherm gas chromatography-mass spectrometry (GC-MS).
for 5% ethyl methacrylate. The presence of Butyl Methacrylate in air can be determined
Fifty percent ethyl methacrylate had a set time of 5.93 min- by gas chromatography. Electron-impact and methane chem-
utes and total exotherm of 76.26 mJ/m2 (see Table 4). The re- ionization mass spectra are used to determine the amount of
sults reported all six test monomers at 50% concentrations had Butyl Methacrylate present in dental materials (HSDB 2000).
faster set times than the 50% ethyl methacrylate standard. The Vapors of Isobutyl Methacrylate can be determined by com-
50% HEMA test monomer took 1.82 minutes to set, which was parison with the condensation of p-methylaminobenzaldehyde
4.13 minutes faster than the set time for 50% ethyl methacry- or p-dimethylaminobenzaldehyde. Isobutyl Methacrylate can
late. HEMA had the highest total exotherm which was 1130.30 also be determined in air by TLC, polarography (used to de-
mJ/m2 , which was 1054.04 mJ/m2 higher than the total exotherm termine residual monomer levels in the polymer), and colorime-
for 5% ethyl methacrylate. Fifty percent 2-Ethoxy Ethoxy Ethyl try. TLC, polarography, and spectrometry are used for solution
Methacrylate had a set time of 5.39 minutes and a total exotherm measurements (HSDB 2001).
of 267.87 which was most similar to 50% ethyl methacrylate. Isobutyl Methacrylate, HEMA, and Di-HEMA Trimethyl-
Faster set times and increased exotherms are strong indicators of hexyl Dicarbamate was analyzed from the liquid monomer of
increased reactivity. The data on the 22 Methacrylates included the light-activated reline material by HPLC with an ultraviolet
in this report have similar levels of reactivity as compared to detector (Kawaguchi et al. 1996).
ethyl methacrylate. Therefore, the polymerization rate and the
amount of unreacted monomer in ethyl methacrylate are similar
Impurities
to the polymerization rate and the amount of unreacted monomer
Certificates of Analysis for other methacrylates used in the
in the Methacrylates included in this report (Creative Nail
artificial nail industry including Butyl Methacrylate, Isobutyl
Design 2001).
Methacrylate, and Lauryl Methacrylate stated that impurities
generally are in the range of less than 0.05%. The only known im-
Method of Manufacture purities are methacrylic acid and other methacrylates and acry-
Butyl Methacrylate is derived from the reaction of lates (ABA/NMC 2001a).
methacrylic acid or methyl methacrylate with butanol (Lewis
1993; HSDB 2000). USE
Isobutyl Methacrylate is derived from the esterification
of isobutyl alcohol with either methacrylic acid or methyl Cosmetic
methacrylate (HSDB 2001). Although some of these ingredients are not currently in the
Methacrylates can also be synthesized by catalytic oxi- International Cosmetic Ingredient Dictionary and Handbook,
dation of isobutylene and subsequent esterification with the they are all used as artificial nail builders in nail enhancement
appropriate alcohol, or by reacting acetone with hydrocyanic products.
 TABLE 1
Definitions and synonyms for methacrylate esters
Ingredient Cas no. Definition Reference Synonyms Reference
Butyl Methacrylate 97-88-1; The ester of n–butyl alcohol Wenninger et al. 2002 Methacrylic acid, butyl ester; Lewis 1993; ChemID 2000;
44914-03-6 plus methacrylic acid that n-butylmethacrylate Hazardous Substances Database
conforms to the formula (HSDB) 2000; Registry of Toxic
in Figure 1 Effects of Chemical Substances
(RTECS), 2000; Wenninger
et al. 2002
Butyl 2-Methacrylate; Butyl ChemID 2000; HSDB 2000;
2-Methyl-2-Propenoate; RTECS 2000; Wenninger et al.
2-Methyl-Butylacrylate; 2002
2-Propenoic Acid, 2-Methyl-,
Butyl Ester
2-Methacrylic acid, butyl ester ChemID 2000
t-Butyl 585-07-9 The ester of t–butyl alcohol ABA and NMC 2001a; Tert-Butyl methacrylate; ChemIDplus 2001
Methacrylate plus methacrylic acid ChemIDplus 2001 Methacrylic acid, tert-butyl ester;
2-Propenoic Acid,
2-Methyl-,1,1-dimethylethyl
ester
Cyclohexyl 101-43-9 The ester of cyclohexyl ABA and NMC 2001a Methacrylic Acid, Cyclohexyl HSDB 2001; ChemIDplus 2001
Methacrylate alcohol plus methacrylic ester; 2-Propenoic Acid,
acid 2-Methyl-, Cyclohexyl Ester
Ethoxyethyl 51289-08-8 The ester of ethoxyethyl ABA and NMC 2001a Not listed ABA and NMC 2001a
Methacrylate alcohol plus methacrylic
acid
2-Ethoxy Ethoxy 45127-97-7 The ester of 2-ethoxy ABA and NMC 2001a 2-(2- Ethoxyethoxy) ethyl ChemIDplus 2001
Ethyl ethoxy ethyl alcohol plus methacrylate
Methacrylate methacrylic acid∗
Ethylene Glycol 97-90-5 Is the organic compound ABA and NMC 2001a 1,2-Bis(Methacryloyloxy)Ethane; HSDB 2001; ChemIDplus 2001
Dimethacrylate that conforms to the Diglycol Dimethacrylate;
formula in Figure 1∗ Ethanediol Dimethacrylate;
Ethyldiol Methacrylate;
Ethylene Glycol
Bis(Methacrylate); Ethylene
Methacrylate; Glycol
Dimethacrylate; Methacrylic
Acid, Ethylene Ester;
2-Propenoic Acid, 2-Methyl-,
1,2-Ethanediyl Ester
Hexyl 101-43-9 The ester of hexyl alcohol ABA and NMC 2001a Hexyl 2-Methyl-2-Propenoate; HSDB 2001; ChemIDplus 2001
Methacrylate plus methacrylic acid∗ Methacrylic Acid, Hexyl Ester;
2-Propenoic Acid, 2-Methyl-,
Hexyl Ester
(Continued on next page)

59
60
TABLE 1
Definitions and Synonyms for Methacrylate Esters (Continued)
Ingredient Cas no. Definition Reference Synonyms Reference
HEMA 868-77-9 is the organic compound Wenninger et al. 2002 2-Hydroxyethyl Methacrylate; HSDB 2001; Wenninger et al.
that conforms to the 2-Propenoic Acid, 2-Methyl-, 2002; ChemIDplus 2001
formula: C6 H10 O3 2-Hydroxyethyl Ester
Ethylene Glycol Methacrylate; HSDB 2001; ChemIDplus 2001
Ethylene Glycol,
Monomethacrylate; Glycol
Methacrylate; Glycol
Monomethacrylate;
Hydroxyethyl Methacrylate;
Beta-Hydroxyethyl
Methacrylate; Methacrylic Acid,
2-Hydroxyethyl Ester;
2-(Methacryloyloxy)Ethanol
Di-HEMA Trimethylhexyl 72869-86-4 Is the organic compound Wenninger et al. 2002 Urethane Dimethacrylate; UDMA; Wenninger et al. 2002;
Dicarbamate that conforms to the 2-Propenoic Acid, 2-Methyl-, ChemIDplus 2001
formula: C23 H38 N2 O8 7,7,9 (or 7,9,9)-Trimethyl-4,
13-Dioxo-3,14-Dioxa-5,12-
Diazahexadecane-1,16-diyl
Ester
Hydroxyethylmethacrylate 21282-97-3 is the organic compound ABA and NMC 2001a 2-(Acetoacetoxy) Ethyl ABA and NMC 2001a
Acetoacetate that conforms to the Methacrylate
formula in Figure 1∗
2-((2-Methyl-1-oxoallyl)oxy)ethyl ChemIDplus 2001
acetoacetate; Butanoic acid,
3-oxo, 2-((2-methyl-1-oxo-2-
propenyl)oxy)ethyl
ester
Hydroxypropyl Methacrylate 27813-02-1 Is the organic compound Wenninger et al. 2002 2-Hydroxypropyl HSDB 2001; Wenninger et al.
that conforms to the Methacrylate;2-Propenoic Acid, 2002; ChemIDplus 2001
formula: C7 H12 O2 2-Methyl-, Monoester with
1,2-Propanediol
Propylene Glycol Wenninger et al. 2002;
Monomethacrylate ChemIDplus 2001
Methacrylic Acid, Monoester with HSDB 2001
1,2-Propanediol;
1,2-Propanediol, 2-Methyl-,
Monomethacrylate; 2-Propenoic
Acid, 2-Methyl-,
2-Hydroxymethylethyl Ester
 Isobornyl Methacrylate 7534-94-3 the ester of isobornyl ABA and NMC 2001a Methacrylic Acid, Isobornyl Ester; HSDB 2001; ChemIDplus 2001
alcohol plus methacrylic 2-Propenoic Acid,
acid 2-Methyl-,1,7,7-
Tirmethylbicyclo(2.2.1)HEPT-2-
YL Ester,
Exo-
Isobutyl Methacrylate 97-86-9 the ester of isobutyl alcohol ChemIDplus 2001 2-Methylpropyl Methacrylate ChemIDplus 2001; HSDB 2001
plus methacrylic acid that
conforms to the formula
in Figure 1
Isobutyl Alpha-Methacrylate; ChemIDplus 2001; HSDB 2001
Isobutyl 2-Methyl-2-Propenoate;
Methacrylic Acid, Isobutyl
Ester; Propenoic Acid,
2-Methyl, Isobutyl Ester;
2-Propenoic Acid, 2-Methyl-,
2-Methylpropyl Ester
2-Methylpropyl ChemIDplus 2001
2-Methyl-2-Propenoate
Isopropylidenediphenyl 1565-94-2 the reaction product that of ABA and NMC 2001a; Bis-GMA;Bisphenol A-glycidyl ChemIDplus 2001
Bisglycidyl Methacrylate bisphenol A and glycidyl ChemIDplus 2001 methacrylate; 2-Propenoic acid,
methacrylate that 2-methyl-,
undergoes (1-methylethylidene)bis(4,1-
polymerization when phenyleneoxy(2-hydroxy-3,1-
exposed to uv light or propanediyl))ester
mixed with a catalyst
Lauryl Methacrylate 142-90-5; 93804-49-0 the ester of lauryl alcohol Wenninger et al. 2002 Dodecyl Methacrylate; Dodecyl ChemID 2000; HSDB 2000;
plus methacrylic acid that 2-Methyl-2-Propenoate RTECS 2000; Wenninger et al.
conforms to the formula 2002
in Figure 1
Methacrylic Acid, Dodecyl Ester HSDB 2000; RTECS 2000;
Wenninger et al. 2002
2-Propenoic Acid, 2-Methyl-, ChemID 2000; HSDB 2000;
Dodecyl Ester Wenninger et al. 2002
2-Methyl-2-Propenoic Acid, Wenninger et al. 2002
Dodecyl Ester
Methacrylic Acid, Lauryl Ester; ChemID 2000; HSDB 2000;
Acrylic Acid, 2-Methyl, RTECS 2000
Dodecyl Ester
Dodecyl-2-Methylacrylate ChemID 2000
Methoxydiglycol Methacrylate 45103-58-0 the ester of ABA and NMC 2001a 2-(2-Methoxyethoxy)ethyl ChemIDplus 2001
methoxydiglycol alcohol methacrylate; 2-Propenoic acid,
plus methacrylic acid 2-methyl-, 2-(2-methoxyethoxy)
ethyl ester
(Continued on next page)

61
62
TABLE 1
Definitions and synonyms for methacrylate esters (Continued)
Ingredient Cas no. Definition Reference Synonyms Reference
PEG-4 Dimethacrylate 109-17-1 Is the organic compound that Wenninger et al. 2002 Tetraethylene Glycol Wenninger et al. 2002
conforms generally to the Dimethacrylate; 2-Propenoic
formula in Figure 1 where Acid, 2-Methyl-, Oxybis (2,1-
n has an average number of Ethanediyloxy-2,1-Ethanediyl)
4. Ester; Polyoxyethylene (4)
Dimethacrylate; Polyethylene
Glycol (4) Dimethacrylate
Pyromellitic Glycidyl 148019-46-9; Is the organic compound that ABA and NMC 2001a Pyromellitic dianhydride glycerol ChemIDplus 2001
Dimethacrylate 146166-65-6 conforms to the formula in dimethacrylate adduct
Figure 1∗
Tetrahydrofurfuryl Methacrylate 2455-24-5 the ester of tetrahydrofurfuryl ABA and NMC 2001a Methacrylic Acid, HSDB 2001; ChemIDplus 2001
alcohol plus methacrylic Tetrahydrofurfuryl Ester;
acid∗ 2-Propenoic Acid, 2-Methyl-,
(Tetrahydro-2-Furanyl)Methyl
Ester
Triethylene Glycol 109-16-0 Is the organic compound that ABA and NMC 2001a 1,2-Bis(2-(Methacryloyloxy) HSDB 2001; ChemIDplus 2001
Dimethacrylate conforms to the formula in Ethoxy)Ethane;
Figure 1 Ethylenebis(Oxyethylene)
Methacrylate; Methacrylic
Acid, Diester with Triethylene
Glycol; 2-Propenoic Acid,
2-Methyl-,
1,2-Ethanediylbis(oxy-2,1-
Ethanediyl) Ester;
TEDMA
Trimethylolpropane 3290-92-4 Is the organic compound that ABA and NMC 2001a Methacrylic acid, triester with ChemIDplus 2001
Trimethacrylate conforms to the formula in 2-ethyl-2-(hydroxymethyl)-
Figure 1 1,3-propanediol;
1,1,1-Trimethylolpropane
Trimethacrylate; 2-Propenoic
Acid, 2-methyl-,
2-ethyl-2-(((2-methyl-1-oxo-2-
propenyl)oxy)methyl)-1,3-
propanediyl
ester
Urethane Methacrylate 65256-52-2 The ester of urethane alcohol ABA and NMC 2001a none ABA and NMC 2001a
plus methacrylic acid*
∗
Unofficial definition; has not yet been established by International Cosmetic Ingredient Dictionary and Handbook
 ESTER MONOMERS USED IN NAIL ENHANCEMENT PRODUCTS 63

TABLE 2
Physical and chemical properties of methacrylate esters
Property Descripton Reference
Butyl Methacrylate
Molecular weight 142.19 Sax 1979; HSDB 2000; Assessment Technologies,
Inc. 1996; Sandmeyer and Kirwin 1981
Appearance/odor Colorless liquid; readily Lewis 1993; Sax 1979; HSDB 2000
polymerizes; ester odor
Boiling point 163.0–170.5◦ C Lewis 1993; Sax 1979; Assessment Technologies,
Inc. 1996
160◦ C HSDB 2000; Sandmeyer and Kirwin 1981
melting point −75◦ C HSDB 2000
density 0.895 Lewis 1993; Sax 1979; HSDB 2000; Assessment
Technologies, Inc. 1996
Flash point 130◦ F (54.4◦ C); 126◦ F Lewis 1993; Sax 1979
106◦ F; 41.1◦ C Sandmeyer and Kirwin 1981
Solubility Insoluble in water Lewis 1993; HSDB 2000; Sandmeyer and Kirwin
1981
Very soluble in alcohol and ether Sandmeyer and Kirwin 1981
Octanol/water partition 2.88 HSDB 2000
coefficient
3.01 Brixham Environmental Lab 1992; Assessment
Technologies, Inc. 1996
1.97 Yoshii 1997
Maximum absorption 214 nm HSDB 2000
t-butyl Methacrylate
Color/form Colorless liquid Lewis 1997
Boiling point 66◦ C Lewis 1997
Density 0.877 Lewis 1997
Flash point 92◦ F Lewis 1997
Isobutyl Methacrylate
Molecular weight 142.20; 142.22 Lewis 2000; HSDB 2001
Color/form Liquid Lewis 1997; HSDB 2001
Boiling point 155◦ C Lewis 1997; HSDB 2001
Melting point −34◦ C Assessment Technologies 1994
Density 0.8858; 0.882 g/ml Lewis 1997; HSDB 2001
Flash point 49◦ C Lewis 1997; HSDB 2001
Solubility >10% in alcohol or ether HSDB 2001
Octanol/water partition 2.66 HSDB 2001
coefficient
1.88 Yoshii 1997
Cyclohexyl Methacrylate
Molecular weight 168.23 HSDB 2001
Color/form Colorless liquid HSDB 2001
Boiling point 210◦ C HSDB 2001; Lewis 1997
Density 0.9626 HSDB 2001; Lewis 1997
Solubility Insoluble in water HSDB 2001
(Continued on next page)
64 COSMETIC INGREDIENT REVIEW

TABLE 2
Physical and Chemical Properties of Methacrylate Esters (Continued)
Property Descripton Reference
Ethylene Glycol Dimethacrylate
Molecular weight 198.22 HSDB 2001
198.1 Lewis 2000
Boiling point 260◦ C HSDB 2001
Melting point −40◦ C HSDB 2001
Density 1.055 HSDB 2001
Solubility >10% in benzene, ethanol, or HSDB 2001
ligroin
Octanol/water partition 1.598 Rustemeyer et al. 1998
coefficient
1.99 Yoshii 1997
Molecular weight 198 Geurtsen 2000
Ethoxyethyl Methacrylate
Octanol/water partition 1.73 Yoshii 1997
coefficient
HEMA
Molecular weight 130.14 HSDB 2001
130 Geurtsen 2000
130.16 Lewis 2000
Color/form Clear mobile liquid HSDB 2001
Boiling point 67◦ C HSDB 2001
71◦ C–73◦ C Lewis 2000
Melting point −12◦ C HSDB 2001
Density 1.034 HSDB 2001
1.064 Lewis 1997
Flash point 97◦ C HSDB 2001
−12◦ C Lewis 1997
Solubility Miscible with water and soluble in HSDB 2001
common organic solvents
Octanol/water partition 0.47 HSDB 2001
coefficient
0.1144 Rustemeyer et al. 1998
0.85 Yoshii 1997
Di-HEMA Trimethylhexyl Dicarbamate
Molecular weight 470 Geurtsen 2000
Hexyl Methacrylate
Molecular weight 170.25 HSDB 2001
Appearance/odor Liquid HSDB 2001
Boiling point 162◦ C HSDB 2001
67◦ –85◦ C Lewis 1997
Density 0.880 HSDB 2001
0.88 Lewis 1997
Solubility >10% in acetone, benzene, ether, HSDB 2001
or ethanol
Hydroxypropyl Methacrylate
Molecular weight 144.18 HSDB 2001
144 Geurtsen 2000
Color/form Clear mobile liquid HSDB 2001
Odor Slightly acrylic odor HSDB 2001
 ESTER MONOMERS USED IN NAIL ENHANCEMENT PRODUCTS 65

TABLE 2
Physical and chemical properties of methacrylate esters (Continued)
Property Descripton Reference
Boiling point 87◦ C HSDB 2001
96◦ C
Melting point −89◦ C HSDB 2001
Density 1.066 HSDB 2001; Lewis 1997
Flash point 250◦ F HSDB 2001
206◦ F Lewis 1997
Solubility Limited solubility in water, soluble HSDB 2001
in common organic solvents
Octanol/water partition 0.4806 Rustemeyer et al. 1998
coefficient
0.79 Yoshii 1997
Isobornyl Methacrylate
Molecular weight 222.33 HSDB 2001
Boiling point 112◦ C–117◦ C HSDB 2001
Density 0.980 HSDB 2001
Isopropylidenediphenyl Bisglycidyl Methacrylate
Molecular weight 512 Björkner 1984a; Geurtsen
2000
Lauryl Methacrylate
Molecular weight 254.41 HSDB 2000
254.8 Assessment Technologies,
Inc. 1996
Boiling point 272–344◦ C Lewis 1993; HSDB 2000
Melting point −20◦ C HSDB 2000
Density 0.868 Lewis 1993; HSDB 2000;
Assessment Technologies,
Inc. 1996
Flash point 270◦ F (132◦ C) Lewis 1993; HSDB 2000
Solubility Insoluble in water HSDB 2000
Octanol/water partition 6.57 Assessment Technologies,
coefficient Inc. 1996
4.68 Yoshii 1997
PEG-4 Dimethacrylate
Molecular weight 330 Björkner 1984c; US EPA
1985
Octanol/water partition 3.61 Yoshii 1997
coefficient
2.06 US EPA 1985
Tetrahydrofurfuryl Methacrylate
Molecular weight 170.208 HSDB 2001
Boiling point 59◦ C–62◦ C HSDB 2001
Octanol/water partition 1.67 Yoshii 1997
coefficient
Triethylene Glycol Dimethacrylate
Molecular weight 286.36 Lewis 2000
286.33 HSDB 2001
286 Geurtsen 2000
286 Björkner 1984c
Boiling point 155◦ C HSDB 2001
66 COSMETIC INGREDIENT REVIEW

TABLE 2
Physical and Chemical Properties of Methacrylate Esters (Continued)
Property Descripton Reference
Density 1.072 HSDB 2001
Solubility >10% in acetone, ethanol, ether, or HSDB 2001
petroleum ether
Octanol/water partition 1.88 HSDB 2001
coefficient
3.05 Yoshii 1997
Trimethylolpropane Trimethacrylate
Molecular weight 338.44 Lewis 2000
338 American Industrial Hygiene Association 1981;
Geurtsen 2000; US EPA 1985
Color/form Amber liquid Lewis 2000
Odor Musty American Industrial Hygiene Association 1981
Boiling point >200◦ C Lewis 2000
>315.5◦ C American Industrial Hygiene Association 1981
Melting point −20 to −10◦ C American Industrial Hygiene Association 1981
Density 0.97 Lewis 2000
Flash point 149◦ F Lewis 2000
>93.3◦ C American Industrial Hygiene Association 1981
Solubility Insoluble in water American Industrial Hygiene Association 1981
Octanol/water partition 3.11 US EPA 1985
coefficient
Urethane Methacrylate
Molecular weight 470 Björkner 1984b

Data submitted to CIR by the Food and Drug Administration as analyzed by GC-MS, but it was not listed on the MSDS for
(FDA) based on industry reports in 2001 do not include any uses this product (Kanerva et al. 1996).
for 21 of the methacrylate esters included in this report. Only Sainio et al. (1997) determined that Butyl Methacrylate was
Tetrahydrofurfuryl Methacrylate was reported to be used in one present in six liquid or dried nail polishes at concentrations that
nail extender product (FDA 2001). Concentration of use data ranged from 0.014–0.067%.
submitted to the FDA in 1984 did not include any uses of these Butyl Methacrylate and Lauryl Methacrylate were not listed
methacrylate esters (FDA 1984). in the Japanese Comprehensive Licensing Standards of Cos-
The industry stated that ethyl methacrylate represents over metics by Category. Neither Butyl Methacrylate nor Lauryl
90% of the monomer used in nail enhancing products while Methacrylate were listed in the 2000 European Economic Com-
Butyl, Isobutyl and Lauryl Methacrylate represent less than 1% munity Cosmetics Directive (European Commission 2000).
of the monomer used in nail enhancing products. The maximum
concentration of use submitted by industry is shown in Table 5 Non-Cosmetic
(ABA/NMC 2001a). Polymeric hydrogels composed of Butyl Methacrylate are
Fisher (1980) and Kanerva et al. (1996) both reported used in drug delivery systems (Katono et al. 1991).
use of Butyl Methacrylate, Isobutyl Methacrylate, Ethylene Butyl Methacrylate was present in orthopedic bone cement
Glycol Dimethacrylate, Tetrahydrofurfuryl Methacrylate, and when analyzed by high-performance liquid chromatography
Trimethylol-propane Trimethacrylate monomers in commercial (HPLC) (Davy and Braden 1991).
nail preparations. Butyl Methacrylate and Lauryl Methacrylate are polymeriz-
Kanerva et al. (1996) reported that Butyl Methacrylate was able monomers used in plastics, molding powders, solvent coat-
present at a concentration of 2.2% in a nail strengthener as an- ings, adhesives, oil additives and emulsions for textile, leather
alyzed by GC-MS, although it was not listed on the material and paper finishing (Lewis 1993; HSDB 2000).
safety data sheet (MSDS) for this product. Butyl Methacrylate is listed as an indirect food addi-
Likewise, Triethylene Glycol Dimethacrylate was present in tive under the following Code of Federal Regulation (CFR)
a monomer liquid for sculptured nails at a concentration of 5% cites: 21CFR175.300, 21CFR176.210 and 21CFR177.2420
 ESTER MONOMERS USED IN NAIL ENHANCEMENT PRODUCTS 67

TABLE 3
Set times and total exotherm data for 22 methacrylates at 5% concentration
Test monomers 1–22 (5% Total exotherm
Sample number concentration) Set time (min) Std. Dev. (%) (mJ/m2 ) Std. Dev. (%)
Standard RadicalTM monomer liquid (neat) 2.78 5.0 650.9 8.0
Standard Ethyl methacrylate (spike) 3.10 4.8 336.58 14.0
1 HEMA 2.85 5.0 672.07 4.4
2 Hydroxypropyl Methacrylate 2.72 6.4 607.16 5.1
3 Methoxydiglycol Methacrylate 2.88 3.3 327.96 3.9
4 Ethoxyethyl Methacrylate 3.63 6.8 367.84 7.6
5 Pyromellitic Glycidyl 2.52 4.6 794.23 3.5
Dimethacrylate
6 Isobornyl Methacrylate 3.27 11.7 342.34 9.3
7 Ethylene Glycol Dimethacrylate 2.97 4.8 405.13 10.3
8 Hydroxyethylmethacrylate 2.86 6 461.5 1.8
Acetoacetate
9 Urethane Methacrylate 2.78 2.1 396.11 7.5
10 Isopropylidenediphenyl 3.03 5.8 302.13 10.9
Bisglycidyl Methacrylate
11 Butyl Methacrylate 3.54 9.7 380.57 6.5
12 Isobutyl Methacrylate 3.53 11.4 362.13 11.1
13 t-butyl Methacrylate 3.82 3.6 285.83 6.9
14 Lauryl Methacrylate 3.6 4.4 308.7 5.8
15 Cyclohexyl Methacrylate 3.2 9.3 313.26 9.3
16 Di-HEMA Trimethylhexyl 2.76 3.9 416.9 10.5
Dicarbamate
17 Hexyl Methacrylate 3.84 5.8 298.77 14.6
18 Triethylene Glycol 2.74 4.4 413.64 9.8
Dimethacrylate
19 Tetrahydrofurfuryl Methacrylate 3.15 7.1 578.7 2.6
20 PEG-4 Dimethacrylate 3.2 8.0 378.66 9.8
21 Trimethylolpropane 2.66 5.3 536.19 3.2
Trimethacrylate
22 2-Ethoxy Ethoxy Ethyl 2.83 4.4 555.10 10.3
Methacrylate

TABLE 4
Set times and total exotherm data for 22 methacrylates at 50% concentration
Test monomers (50% Total exotherm
Sample number concentration) Set time (min) Std. Dev. (%) (mJ/m2 ) Std. Dev. (%)
Standard RadicalTM monomer liquid 2.78 5.0 650.9 8.0
(standard)
Standard Ethyl methacrylate (standard) 5.93 27.8 76.26 52.9
1 HEMA 1.82 1.0 1130.30 6.3
2 Hydroxypropyl Methacrylate 2.25 3.9 785.00 5.0
3 Methoxydiglycol Methacrylate 5.11 1.3 111.78 1.7
4 Ethoxyethyl Methacrylate 4.35 3.2 136.16 7.2
19 Tetrahydrofurfuryl Methacrylate 3.82 7.6 546.1 10.3
22 2-Ethoxy Ethoxy Ethyl 5.39 4.0 267.87 9.1
Methacrylate
68 COSMETIC INGREDIENT REVIEW

TABLE 5 lubricating oil and for pour-paint depressants for distillate fuels.
Concentration of use data for methacrylate esters in nail Lauryl Methacrylate is used in dentistry as restorative material,
enhancement products submitted by ABA/NMC (2001a) adhesive and prosthetic device (HSDB 2000).
A variety of methacrylates are used in printing and as dental
Maximum use resins (Bong and English 2000).
Methacrylate esters concentration (%)
HEMA 30 GENERAL BIOLOGY
Hydroxypropyl Methacrylate 25
Absorption, Distribution, Metabolism and Excretion
Methoxydiglycol Methacrylate 85
Ethoxyethyl Methacrylate 85 The absorption, distribution, and excretion of 14 C labeled Tri-
Pyromellitic Glycidyl 5 ethylene Glycol Dimethacrylate was measured 24 hours after
Dimethacrylate administration to guinea pigs and mice. Guinea pigs received
Isobornyl Methacrylate 5 0.02 mmol/kg 14 C labeled Triethylene Glycol Dimethacrylate
Ethylene Glycol Dimethacrylate 5 by subcutaneous injection or gastric tube. Mice received a
Hydroxyethylmethacrylate 10 0.1 ml volume of 10 nanomoles 14 C labeled Triethylene Gly-
Acetoacetate col Dimethacrylate by gastric tube, subcutaneous injection, and
Urethane Methacrylate 3 iv injection (Reichl et al. 2001a).
Isopropylidenediphenyl Bisglycidyl 5 After guinea pigs were exposed for 24 hours, approximately
Methacrylate 80% of radiolabel was recovered (60% by air, 15% by urine, and
Butyl Methacrylate 7 5% in tissues). After 24 hours, virtually all detectable 14 C was
Isobutyl Methacrylate 10 cleared from mice exposed to Triethylene Glycol Dimethacry-
t-butyl Methacrylate 7 late by gastric and subcutaneous administration. However, trace
Lauryl Methacrylate 5 amounts of 14 C were present in mice exposed by iv injection of
Cyclohexyl Methacrylate 2 Triethylene Glycol Dimethacrylate. The authors assumed if the
Di-HEMA Trimethylhexyl 3 metabolism and clearance of Triethylene Glycol Dimethacry-
Dicarbamate late in humans is similar to those of guinea pigs, then it is highly
Hexyl Methacrylate 5 unlikely that Triethylene Glycol Dimethacrylate released from
Triethylene Glycol Dimethacrylate 7 dental restorative materials in humans could have systemic toxic
Tetrahydrofurfuryl Methacrylate 7 effects.
PEG-4 Dimethacrylate 15 The methacrylates are metabolized via two basic pathways,
Trimethylolpropane 5 hydrolysis and conjugation (Greim et al. 1995).
Trimethacrylate In order to measure enzymatic hydrolysis, Butyl Methacry-
2-Ethoxy Ethoxy Ethyl 75 late was incubated with purified porcine liver carboxylesterase
Methacrylate stock solution. The volume of carboxylesterase stock solution
(10.7 μg/ml) added to the solution was adjusted for each ex-
periment to standardize the enzymatic activity of the samples.
Butyl Methacrylate, at a concentration of 5 to 250 μM (n = 5)
(Wenninger et al. 2002). Butyl Methacrylate monomer and had a Km of 72 ± 28 μM, a Vmax of 1.84 ± 0.64 nmol/min
copolymer are used in dental technology, as components in oil and a Vmax /Km ratio of 26 l/min. The investigators concluded
dispersible pesticides and as copolymers in paraffin embedding that α-methyl substitution does not have a significant effect on
media. The monomer is used in the manufacture of contact lenses hydrolysis in comparison with the acrylate analog (McCarthy
and acrylic surface coatings (HSDB 2000). and Witz 1997).
Isobutyl Methacrylate is used as monomer for acrylic resins
in dental applications, in hydrogel contact lenses, and with vinyl Cytotoxicity
monomers in concrete to increase its water repellence (Zuccari Foong et al. (1990) presented a preliminary study in which
et al. 1997; HSDB 2001). the cytotoxicity of Butyl Methacrylate and Lauryl Methacry-
A liquid monomer containing 70% Isobutyl Methacrylate, late was determined in the liposome-neutral red cytotoxicity
15% HEMA, and 15% Trimethylolpropane Trimethacrylate by test. The concentration effect of liposome entrapped compounds
weight, is used in light-activated reline materials to improve the on the neutral red (NR) content of NIH 3T3 cells was mea-
fit of dentures after prolonged usage. There is some leaching of sured spectrophotometrically. Butyl Methacrylate and Lauryl
unreacted monomer (Kawaguchi et al. 1996). Methacrylate were tested at five concentrations of 1 μM to 10
Lauryl Methacrylate is also used as a deodorant to mask mM. The negative controls were DMEM (Dulbecco’s modified
methyl sulfide odors in industry, to delay volatilization of eagle medium), phosphate buffered saline and empty liposomes.
insecticides, as a monomer for viscosity index improvers for Neutral red absorbance at all test sample concentrations showed
 ESTER MONOMERS USED IN NAIL ENHANCEMENT PRODUCTS 69

that Butyl Methacrylate and Lauryl Methacrylate were less toxic cells were 135 (0.068 M), 220 (1.692 M), 39 (0.681 M), and
than the positive control (dibutyl tin diacetate). A dose depen- 400 μg/ml (1.398 M), respectively. The IC50 values for Ethylene
dent concentration effect was observed for each compound. A Glycol Dimethacrylate, HEMA, Isopropylidenediphenyl Bisg-
significant difference between Butyl Methacrylate and Lauryl lycidyl Methacrylate, and Triethylene Glycol Dimethacrylate
Methacrylate was observed at 0.01 M. Lauryl Methacrylate was with S9 in JTC-12 cells were <200 (<0.425 M), 500 (3.842
more toxic than Butyl Methacrylate and was ranked just beneath M), 820 (4.141 M), and <1000 μg/ml (<3.496 M), respectively
the positive control, which may be related to its high molecular (Hikage et al. 1999).
weight. Geurtsen et al. (1998) investigated the cytotoxic ef-
Benson and Stackhouse (1986) performed a bacterial lumi- fects of Ethylene Glycol Dimethacrylate, HEMA, Isopropy-
nescence inhibition assay (an alternative assay to assess the tox- lidenediphenyl Bisglycidyl Methacrylate, Triethylene Glycol
icity of compounds) using Photobacterium phosphoreum and Dimethacrylate, and Di-HEMA Trimethylhexyl Dicarbamate
six consecutive concentrations of Butyl Methacrylate which in- using monolayers of permanent 3T3 cells and three primary
creased by a factor of 1.5 on a mg/kg basis. After 5, 15 and human fibroblast types derived from oral tissues (gingiva, pulp,
30 min of incubation, light measurements were performed. A and periodontal). Primary human periodontal ligament and pulp
control was also used to correct for time-dependent drift in light fibroblasts were found to be more sensitive than 3T3 and gingival
output. The concentration that inhibited luminescence by 50% fibroblasts.
was 37, 49 and 55 mg/L (at 5, 15 and 30 min, respectively). The methacrylate monomers tested had ED50 values that
Reichl et al. (2001b) investigated the effect of Triethylene ranged from 0.06 to 2.52 mM. The most toxic methacry-
Glycol Dimethacrylate and HEMA on the release of lactate de- lates tested were Isopropylidenediphenyl Bisglycidyl Methacry-
hydrogenase (LDH) from alveolar lung cell lines in vitro. Con- late (0.08–0.14 mM), Di-HEMA Trimethylhexyl Dicarbamate
fluent layers of A549 cells (human, malignant) and L2 rat cells (0.06–0.47 mM), and Triethylene Glycol Dimethacrylate (0.12–
were incubated with various concentrations of Triethylene Gly- 0.26 mM). Ethylene Glycol Dimethacrylate (0.46–2.31 mM) and
col Dimethacrylate and HEMA for 8 hours (and up to 48 hours HEMA (1.77-2.52 mM) were moderately toxic (Geurtsen et al.
for L2 cells) at 37◦ C. LDH release was measured and an EC50 1998).
was calculated. Yoshii (1997) evaluated the cytotoxicity of Butyl Methacry-
A significant increase in LDH release was found in the L2 late, Isobutyl Methacrylate, Ethoxyethyl Methacrylate, Ethylene
cells after an 8-hour incubation with HEMA (4 mmol/l) and Tri- Glycol Dimethacrylate, HEMA, Hydroxypropyl Methacrylate,
ethylene Glycol Dimethacrylate (2 mmol/l) and in A549 cells Isopropylidenediphenyl Bisglycidyl Methacrylate, Lauryl
with HEMA (14 mmol/l) and Triethylene Glycol Dimethacry- Methacrylate, PEG-4 Dimethacrylate, Tetrahydrofurfuryl
late (15 mmol/l). In L2 cells, the EC50 for HEMA at 6, 12, 24, 36, Methacrylate, Triethylene Glycol Dimethacrylate, and Di-
and 48 hours was 5.46, 4.66, 3.68, 3.22, and 0.59 mmol/l, respec- HEMA Trimethylhexyl Dicarbamate in the 3-(4,5-dimethyl-2-
tively. In L2 cells, the EC50 for Triethylene Glycol Dimethacry- thiazolyl)-2,5-diphenyl-2H tetrazorium bromide (MTT) assay
late at 6, 12, 24, 36, and 48 hours was 3.37, 1.30, 1.47, 1.58, and using HeLa S3 cells. The IC50 of each chemical was determined.
0.42 mmol/l, respectively (Reichl et al. 2001b). The ranking of monomers in order of decreasing cyto-
Hikage et al. (1999) evaluated the cytotoxicity of Ethylene toxicity was Isopropylidenediphenyl Bisglycidyl Methacry-
Glycol Dimethacrylate, HEMA, Isopropylidenediphenyl Bisg- late (0.03 mmol/l), Di-HEMA Trimethylhexyl Dicarba-
lycidyl Methacrylate, and Triethylene Glycol Dimethacrylate in mate (0.09 mmol/l), Lauryl Methacrylate (0.67 mmol/l),
the presence of rat liver S9 mix containing cytochrome P450 en- Ethylene Glycol Dimethacrylate (1.06 mmol/l), Triethylene
zymes. JTC-12 cells derived from a monkey kidney were added Glycol Dimethacrylate (1.50 mmol/l), PEG-4 Dimethacry-
to a 96-well plate. After cultivation, S9 was added to some wells late (1.97 mmol/l), Butyl Methacrylate (2.71 mmol/l),
and PBS was added to cells not receiving S9, then 7 different con- Ethoxyethyl Methacrylate (2.72 mmol/l), Isobutyl Methacrylate
centrations of either Ethylene Glycol Dimethacrylate, HEMA, (2.94 mmol/l), Tetrahydrofurfuryl Methacrylate (4.70 mmol/l),
Isopropylidenediphenyl Bisglycidyl Methacrylate, or Triethy- Hydroxypropyl Methacrylate (8.67 mmol/l), and HEMA
lene Glycol Dimethacrylate were added to each well. The cell (10.07 mmol/l). In comparison, the IC50 of ethyl methacrylate
survival ratio (CSR) was calculated by using a neutral red cyto- was 29.26 mmol/l (Yoshii 1997).
toxicity assay after 24 hours. Bouillaguet et al. (2000) evaluated the HEMA effects on
The CSR for 50 μg/ml of Isopropylidenediphenyl Bisgly- human THP-1 monocyte-macrophages by measuring cellular
cidyl Methacrylate with S9 mix was 92.6%, and without S9 proliferation using the trypan-blue exclusion assay, mitochon-
mix was 6.6%. The CSR for Ethylene Glycol Dimethacrylate, drial activity as measured by the MTT assay, and total cel-
HEMA, and Triethylene Glycol Dimethacrylate exhibited a sta- lular protein as measured by the bicinchoninic assay. Human
tistically significant reduction in cytotoxicity in the presence of THP-1 monocyte-macrophages were exposed to HEMA for up
S9 mixture. The IC50 values for Ethylene Glycol Dimethacry- to 6 weeks at concentrations of 0 to 1.5 mmol/l.
late, HEMA, Isopropylidenediphenyl Bisglycidyl Methacrylate, Macrophage proliferation was inhibited by 40 to 50% by
and Triethylene Glycol Dimethacrylate without S9 in JTC-12 as little as 0.75 mmol/l HEMA after 1 week of exposure and
70 COSMETIC INGREDIENT REVIEW

remained constant. Total protein per cell increased by as much as control. The endocrine disrupting activity was assessed using
80% after 2 weeks and remained elevated for the remainder of the three in vitro tests: the yeast two-hybrid system, a fluorescence
study. Mitochondrial activity per cell was increased by 60 to 80% polarization system, and MCF-7 cell growth in the E-Screen
after 2 weeks and then decreased but remained elevated above test. HEMA, Isopropylidenediphenyl Bisglycidyl Methacrylate,
control levels for the entire study. The authors noted concentra- Trimethylolpropane Trimethacrylate, and Di-HEMA Trimethyl-
tions as low as 0.5 mmol/l of HEMA could significantly alter hexyl Dicarbamate did not have any estrogenic activity.
the proliferation and activity of human monocyte-macrophages, Olea et al. (1996) determined the estrogenic activity of an Iso-
which is substantially lower levels than those previously identi- propylidenediphenyl Bisglycidyl Methacrylate dental sealant in
fied in conventional 24 to 72-hour cell-culture tests (Bouillaguet MCF7 human breast cancer cells. Cell proliferation in MCF7
et al. 2000). cells was measured for up to 144 hours in the presence of Iso-
Chirila et al. (1991) evaluated the cytotoxicity of Ethoxyethyl propylidenediphenyl Bisglycidyl Methacrylate and other den-
Methacrylate and HEMA in the trypan blue analysis, LDH assay, tal composites. The dental sealant increased cell yields, pro-
and inhibition of DNA synthesis assay. HEMA and Ethoxyethyl gesterone receptor expression, and pS2 secretion in human
Methacrylate were tested at concentrations from 0.025% to 0.50 estrogen-target, serum-sensitive MCF7 breast cancer cells.
and 0.025% to 0.15%, respectively. Isopropylidenediphenyl Bisglycidyl Methacrylate itself,
HEMA was much more toxic than Ethoxyethyl Methacry- however, was negative in the estrogenicity test at concentra-
late at similar concentrations. In the LDH assay, 0.10% tions from 10−9 to 10−5 M. Bisphenol-A and its dimethacrylate
HEMA caused 66.6 ± 2.4% cell death. In comparison, 0.10% (monomers found in the base paste of the dental sealant) were
Ethoxyethyl Methacrylate caused 6.6 ± 1.5% cell death after a estrogenic when assayed in the breast cancer cell proliferation
48 hour incubation. Both HEMA and Ethoxyethyl Methacry- assay. The concentration required to produce maximum pro-
late inhibited DNA synthesis in a dose-dependent manner, but liferation of MCF7 cells was 10,000-fold higher than those of
Ethoxyethyl Methacrylate was nontoxic by trypan blue assay. Estradiol-17β. Eighteen dental patients treated with 50 mg of an
Ethoxyethyl Methacrylate was considered “virtually nontoxic Isopropylidenediphenyl Bisglycidyl Methacrylate-based dental
over the concentration tested” (Chirila et al. 1991). sealant on their molars had bisphenol-A (range 90–931 μg) in
Ratanasathien et al. (1995) evaluated the cytotoxicity of saliva one hour after treatment (Olea et al. 1996).
HEMA, Isopropylidenediphenyl Bisglycidyl Methacrylate, Tri-
ethylene Glycol Dimethacrylate, and Di-HEMA Trimethylhexyl Effects on Red Blood Cells
Dicarbamate in cultures of Balb/c 3T3 mouse fibroblasts. The Butyl Methacrylate (100 mM), PEG-4 Dimethacrylate (10
TC50 values were significantly decreased at 72 hours compared mM), or Tetraethylene Glycol Dimethacrylate (10 mM) was in-
with 24 hours. The TC50 value of HEMA was 3600 μmol/l cubated with 0.25 mM glutathione (GSH) for up to 45 min and
at 24 hours and 1025 μmol/l at 72 hours. The rank of TC50 red blood cell suspensions from female Sprague-Dawley rats
values was the same at both 24 and 72 hours of exposure: Iso- for one hour. Controls were included for the latter experiment.
propylidenediphenyl Bisglycidyl Methacrylate (most toxic) > Butyl Methacrylate did not react with GSH to any apprecia-
Di-HEMA Trimethylhexyl Dicarbamate > Triethylene Glycol ble extent in the cell-free system; however PEG-4 Dimethacry-
Dimethacrylate > HEMA (least toxic). late and Tetraethylene Glycol Dimethacrylate had apparent rate
Gough and Downes (2001) assessed the cytoxicity of Tetrahy- constants of 1.45 and 0.83 liter mol−1 min−1 . Data indicated
drofurfuryl Methacrylate in human osteoblast cells. Cells were that α-methyl substitution greatly decreased monofunctional
treated with Tetrahydrofurfuryl Methacrylate at a range of con- methacrylate activity to nucleophiles. Rat red blood cells incu-
centrations; at various time points cell activity was measured bated with acrylates had linear GSH depletion curves over time
using the Alamar Blue assay, and apoptosis was determined for Butyl Methacrylate, PEG-4 Dimethacrylate and Tetraethy-
by Hoechst staining. Cells stained with Hoechst after culture lene Glycol Dimethacrylate (McCarthy et al. 1994).
in Tetrahydrofurfuryl Methacrylate had apoptotic morphology
dependent on concentration. Cells cultured in a 1 in 5000 di- ANIMAL TOXICOLOGY
lution (1.224 mM) of Tetrahydrofurfuryl Methacrylate showed
typical apoptotic morphology. Cells cultured in a 1 in 20,000 Acute Butyl Methacrylate Toxicity
(0.306 mM) dilution did not show any evidence of apoptosis, Oral
but mitotic figures were observed. Deichmann (1941) dosed 20 rats orally with 17.9 g/kg body
weight Butyl Methacrylate. Only 2/20 rats died within 10–36
Estrogenic Activity h. Six rabbits (1 rabbit per group) were dosed orally with 5.37
Hashimoto and Nakamura (2000) assessed the estro- to 10.74 g/kg Butyl Methacrylate. Only the rabbits treated with
genic activity of HEMA, Isopropylidene-diphenyl Bisglycidyl 5.37 and 8.06 g/kg Butyl Methacrylate survived. All other an-
Methacrylate, Trimethylol-propane Trimethacrylate, and Di- imals died within 12–36 h. Butyl Methacrylate did not have
HEMA Trimethylhexyl Dicarbamate at concentrations ranging an effect on the blood or hemoglobin of rats or rabbits. In
from 10−7 to 10−3 M. 17β-Estradiol at 10−7 was the positive both rats and rabbits, oral lethal doses of Butyl Methacrylate
 ESTER MONOMERS USED IN NAIL ENHANCEMENT PRODUCTS 71

(17.90 g/kg in rats and 6.27–9.00 g/kg in rabbits from 10–36 Eastman Kodak Co. (1984) reported that the oral LD50 for
hours post-administration) produced pronounced increased res- Butyl Methacrylate in rats and mice was >3200 mg/kg. The ip
piration rates (with lacrimation in rats) in 2–5 minutes, followed LD50 for Butyl Methacrylate in rats and mice was >3200 mg/kg
by motor weakness and decreased respiration (15–40 minutes and 1600 mg/kg, respectively.
later). There was increased defecation and urination and reflex
activity was lost and the animals died in coma. Intravenous (iv)
The oral LD50 of Butyl Methacrylate in rats was reported as Deichmann (1941) injected anesthetized rabbits iv with 0.03
>20 g/kg (Autian 1975). or 0.04 cc/kg Butyl Methacrylate. Blood pressure changes and
E.I. Dupont de Nemours & Co. (1993) reported on 5 male and respiration rates were recorded for a planned one-hour sur-
five female rats administered a single oral dose of 2000 mg/kg vival period. Butyl Methacrylate produced a prompt and sud-
Butyl Methacrylate. No rats died during the study. The LD50 den fall in arterial pressure followed by recovery in 3 to 4
was >2000 mg/kg. No clinical signs of toxicity were observed min. Respiration was immediately stimulated and remained at
during the 14-day recovery period. No compound related gross an elevated rate for about 20–30 min. Respiration decreased
abnormalities were observed at necropsy and no target organ was with each additional sublethal dose (1–2 doses max) until it fi-
identified. Butyl Methacrylate was considered slightly toxic. nally stopped. Oral and subcutaneous administration of Butyl
Greim et al. (1995) stated that the oral LD50 for Butyl Methacrylate produced the same changes but the onset was less
Methacrylate in rats was >5000 mg/kg. significant.
Mir et al. (1974) reported a study in which male mongrel dogs
Intraperitoneal (ip) (9–12 kg; 3 dogs/group) were anesthetized and given 0.0207 ml
Sandmeyer and Kirwin (1981) stated that the ip LD50 for (135 × 10−6 M), 0.0415 ml (270 × 10−6 M), 0.0830 ml (540 ×
Butyl Methacrylate in rats was 2.3 g/kg. The ip LD50 for Butyl 10−6 M), or 0.1660 ml (1080 × 10−6 M) Butyl Methacrylate
Methacrylate in mice was 1.49 g/kg. intravenously (iv). Blood pressure, heart rate, electrocardiogram
The ip LD50 of Butyl Methacrylate in mice was reported and respiration rate were measured.
as 1.663 ml/kg or 10.481 mole/106 g (Lawrence et al. 1972; The highest dose was rapidly fatal to the dogs. Following
Autian 1975). Lawrence et al. (1972) stated that acrylate injection of Butyl Methacrylate, an abrupt decrease in systemic
monomers were more toxic than the corresponding methacrylate pressure (18–39%) occurred which lasted for 2 to 4 min at all
monomers. The lower molecular weight members of the acry- doses. The pressure increased slowly and reached a plateau at
late/methacrylate series were more toxic than the higher molecu- higher than control values for 10–15 min. Heart rate decreased
lar weight members. Additionally, the straight chain substituent at all dose levels compared to control values, the percent change
was less toxic than the corresponding branched chain, and sim- ranged from 13–27%. Respiratory rate increased at all dose lev-
ple aliphatic substituents were less toxic than substituents that els of Butyl Methacrylate, the percent change ranged from 164–
contained hydroxyl or amine functional groups. 303%. Dose-related cardiac responses included the following:
Singh et al. (1972) administered a single ip injection of Butyl bradycardia, a reduced rate of impulse transmission through the
Methacrylate to Sprague-Dawley rats and observed the animals A-V node, and possible acute cardiac ischemia. Higher doses
for mortality over seven days. The ip LD50 for Butyl Methacry- produced premature ventricular contractions and incomplete A-
late was reported as 2.3039 ml/kg (95% confidence limits were V block (Mir et al. 1974).
1.8811–2.8217 ml/kg).
The acute ip LD50 for Butyl Methacrylate in the mouse was Intraperitoneal/Intravenous
1.663 ml/kg (10.481 moles/106 g) (Mir et al. 1973a). Swiss Webster mice (1/group) were dosed ip and iv with 6
consecutive doses of Butyl Methacrylate that differed by a factor
Oral/Intraperitoneal of 1.5 mg/kg. Animals were observed for 48 h after administra-
Lawrence et al. (1974) determined the oral and ip LD50 s for tion of Butyl Methacrylate. The approximate lethal dose for ip
Butyl Methacrylate using mice and rats (10 and 2 animals/group, and iv administration was 1000 and 100 mg/kg, respectively
respectively). The oral or ip doses were 0.5, 1, 2, 4, 8 or 16 ml/kg. (Benson and Stackhouse 1986).
Animals were given a single dose of Butyl Methacrylate and
observed for 7 days for signs of toxicity. The oral and ip LD50 s Dermal
for mice were 16.00 ml/kg and 1.66 ml/kg (10 mice/group), Deichmann (1941) prepared the skin of the abdomen of rab-
respectively. The oral and ip LD50 s for rats were >16.00 ml/kg bits by clipping the hair. The animals were restrained so that they
and 5.7 ml/kg, respectively. could not inhale the vapor of Butyl Methacrylate. The compound
Sandmeyer and Kirwin (1981) stated that the oral LD50 for was dropped onto the clipped area in single doses of 10 cc/kg.
Butyl Methacrylate in rats was >20 g/kg. The ip LD50 for Butyl Methacrylate produced malaise and temporary local ir-
Butyl Methacrylate in rats was 2.3 g/kg. The ip LD50 for Butyl ritation, but the animals recovered within an hour. In a review,
Methacrylate in mice was 1.49 g/kg. The oral LD50 for Butyl Gould (1987) stated that Butyl Methacrylate causes acute dermal
Methacrylate in rabbits was >6.3 g/kg. irritation to rabbits.
72 COSMETIC INGREDIENT REVIEW

The dermal LD50 of Butyl Methacrylate in rabbits was re- No significant gross abnormalities of the major organs were
ported as >10 ml/kg (Autian 1975). Greim et al. (1995) stated observed at necropsy. The LC50 value calculated for 24-h sur-
that the dermal LD50 for rabbits was >2000 mg/kg. vivors for Butyl Methacrylate was 4910 ppm (4223-5709 ppm).
The dermal LD50 for Butyl Methacrylate in three guinea pigs The investigators suggested that Butyl Methacrylate is more
was reported as >20 ml/kg (Eastman Kodak Co. 1984). Guinea toxic than methyl or ethyl methacrylate (Oberly and Tansy
pigs were dosed with 5-20 ml/kg using an occluded application 1985).
protocol. At 24 h, there was moderate edema and erythema with The Haskell Laboratory (1993a) exposed male Swiss Webster
hemorrhagic patch areas. At one week, heavy desquamation and mice (4/group) to 490, 980, 6300 or 20000 ppm Butyl Methacry-
light flakey eschars were evident on most of the patch area. By late for 30 min in an inhalation chamber. Respiratory rates were
week two scattered scarring was observed. recorded every 15 seconds during exposure and the 10 min pos-
texposure period.
Subcutaneous Mice exposed to the lowest concentration tested had spo-
A dose of 25 cc/kg of Butyl Methacrylate given to ten rats radic breathing patterns of mild sensory irritation for the first
subcutaneously caused no fatalities. Butyl Methacrylate did not few minutes. An initial decrease in respiratory rate occurred in
have an apparent effect on the blood or hemoglobin of treated all groups of mice exposed to Butyl Methacrylate. Respiratory
rats (Deichmann 1941). rates remained lower than pre-exposure rates throughout the ex-
posure period; however, there was no concentration-response
Inhalation relationship.
Deichmann (1941) exposed rats to 2.9, 3.4, 4.0 or 5.0 mg/L Maximum decreases ranged from 15.4 to 19.7%. Breathing
Butyl Methacrylate for 8 h, although the investigators state frequencies increased during the post exposure period. The in-
that it was impossible to obtain concentrations above 3 mg/L vestigators concluded that Butyl Methacrylate does not act as a
in air. All animals survived and the treated animals had ir- sensory or pulmonary irritant. An RD50 value was not calculated
ritation of the mucous membranes, malaise and accelerated (Haskell Laboratory 1993a).
respiration. The Haskell Laboratory (1993b) also exposed six groups of
Gross pathology was confined primarily to the respiratory five male and five female rats via inhalation to 14 ± 0.94, 18 ±
system. The lungs, trachea and bronchi of treated rabbits, guinea 3.6, 24 ± 2.0, 27 ± 2.2, 29 ± 0.98 and 36 ± 1.5 mg/L Butyl
pigs and rats were markedly congested, edematous and spotted Methacrylate for a four hour period. All rats were restrained
with large and small areas of hemorrhage and emphysema. The in perforated, stainless steel or polycarbonate cylinders with
ventricles were usually well contracted and the auricles were conical nose pieces. Only the nose of each rat extended into
dilated and filled with dark clotted blood. The urinary bladder the exposure chamber. A control group was not included in the
of rats was greatly distended and often contained blood. Ad- study.
ditionally, oral administration produced pronounced corrosion, All rats in the 14, 18, 24 and 27 mg/L groups survived the
areas of hemorrhage and detachment of the gastric mucosa. The exposure and recovery period. Following exposure, clinical ob-
intestine had congestion and acute irritation of the mucosa (De- servations included abnormal gait (24 mg/L only), discharge,
ichmann 1941). diarrhea, hunched posture, irregular respiration, lethargy, lung
Inhalation toxicity in ICR mice was conducted by bubbling noise, tremors (one female in the 18 mg/L group) and wet fur.
air through Butyl Methacrylate at a rate of 2 L/min. None of Stained fur, corneal opacity and weakness developed during the
the five mice exposed to 17.01 mg/L Butyl Methacrylate for recovery period. In the 29 mg/L group one male and one female
455.63 minutes died as a result of exposure to Butyl Methacry- rat died during exposure and on test day 2, two male rats and
late (Lawrence et al. 1974). two female rats were found dead.
Oberly and Tansy (1985) exposed rats to Butyl Methacrylate Clinical observations were similar to the lower concentration
vapors. Six dose groups (3003, 4015, 4397, 5025, 5999 and 7083 groups and also included gasping, swollen nose, wet fur, ruffled
ppm) of 10 male Sprague-Dawley rats were exposed to vapors and stained fur and soreness. No high dose rats died during
of Butyl Methacrylate for a four-hour period. A sham or control exposure; however, three female rats were found dead on test
group was also included. day 2. Clinical observations were similar to those of the other
Survival decreased as concentration increased; however, all dose groups. Both male and female rats in all groups initially
animals that survived the first 24 h survived the 14-day obser- lost weight after exposure to Butyl Methacrylate, with more
vation period. Upon exposure to Butyl Methacrylate vapors, the severe weight loss in the higher dose groups. The 29 mg/L group
animals began to squint and huddle, the remainder of the expo- continued to gain weight throughout the 15 days when body
sure period their behavior suggested irritation to the eyes, nose weights were recorded and by day 15 weighed more than at
and respiratory tract with labored breathing apparent during part study start, while all other groups lost weight.
of the exposure interval. Blanching of the ears and paws sug- Although an LC50 could not be calculated, the approxi-
gested death was imminent. Death was attributed to generalized mate lethal concentration for Butyl Methacrylate was 29 mg/L.
cardiopulmonary collapse. The investigators concluded that Butyl Methacrylate has a low
 ESTER MONOMERS USED IN NAIL ENHANCEMENT PRODUCTS 73

toxicity on an acute inhalation basis (Haskell Laboratory Intraperitoneal

1993b). Lewis (2000) listed the Ethylene Glycol Dimethacrylate ip
The 4 h LC50 for rats exposed to Butyl Methacrylate was LD50 in the rat as 2800 mg/kg. No details were available.
28,469 mg/m3 (Greim et al. 1995).
Acute HEMA Toxicity
In vitro Oral
Mir et al. (1973a) perfused isolated rabbit hearts in vitro with Lewis (2000) listed the HEMA oral LD50 in the rat as
1:100,000, 1:10,000 or 1:1000 dilutions of Butyl Methacrylate. 5050 mg/kg and the oral LD50 in the mouse as 3275 mg/kg.
Butyl Methacrylate was tested five times but the number of hearts No details were available.
used was not available. The procedure used a uniform hydro-
static pressure that provided a constant perfusion pressure. Each Intraperitoneal/Intramuscular
heart was perfused for a 20 min equilibration period and the test
The ip LD50 of HEMA in mice was reported as 0.497 ml/kg
was conducted over the following 90 min. The test solution was
or 4.060 mole/106 g (Lawrence et al. 1972; Autian 1975).
introduced as the perfusate for one minute after cardiac activity
Schneiderka et al. (1996) dosed female Wistar rats (8 weeks
had stabilized and then normal Locke’s solution was perfused
old/ 200 grams) with HEMA intramuscularly or ip. Six doses
to permit recovery of the heart. The effect was considered irre-
of the monomer were chosen for administration to 10 animals
versible if cardiac activity did not return significantly to control
each. Lethal doses were calculated.
levels within 30 to 35 min of perfusion with normal Locke’s
The HEMA ip LD0.02 , LD0.2 , LD2.0 , LD10 , LD25 , LD50 ,
solution.
and LD90 in rats were calculated to be 0.048, 0.087, 0.180,
Butyl Methacrylate produced an irreversible effect on the
0.358, 0.612, 1.110, 3.450 ml/kg, respectively. The HEMA
isolated heart at only the highest concentration. The lowest con-
intramuscular LD0.02 , LD0.2 , LD2.0 , LD10 , LD25 , LD50 , and
centration did not change the cardiac rate per minute, force of
LD90 in rats were calculated to be 2.164, 2.296, 2.471, 2.650,
contraction or coronary flow. The cardiac rate per minute, force
2.791, 2.970, and 3.330 ml/kg, respectively (Schneiderka et al.
of contraction (g) and coronary flow (ml/min) were significantly
1996).
decreased at all concentrations tested compared to control. The
Lewis (2000) listed the HEMA oral LD50 in the rat as
only exception was that coronary flow was not significantly af-
1250 mg/kg and the oral LD50 in the mouse as 497 mg/kg. No
fected at the lowest Butyl Methacrylate concentration tested (Mir
details were available.
et al. 1973a).
Mir et al. (1973b) exposed newly isolated guinea pig ileum of
Intravenous
either sex to Butyl Methacrylate one time at dilutions of 1:2000,
1:1000 or 1:500. The number of samples used was not specified. Mir et al. (1974) reported a study in which male mongrel dogs
The spontaneous activity of the intestine to Tyrode’s solution was (9-12 kg; 3 dogs/group) were anesthetized and given 0.0124 ml
recorded and then Butyl Methacrylate was added to the bath and (101 × 10−6 M), 0.0248 ml (202 × 10−6 M), 0.0496 ml (404 ×
the response recorded. 10−6 M), or 0.0992 ml (808 × 10−6 M) HEMA by iv injection.
Butyl Methacrylate produced a concentration-dependent de- Blood pressure, heart rate, electrocardiogram and respiration
pressant effect upon spontaneous motility of the isolated guinea rate were measured.
pig ileum. Additionally, a concentration-dependent antagonism The highest dose was rapidly fatal to the dogs. Following
of the neurogenic and myogenic stimulant effects of acetyl- injection of HEMA, an abrupt decrease in systemic pressure
choline (1:10,000,000) and barium chloride (3:100,000) was (29-54%) occurred which lasted for 2 to 4 min at all doses.
observed upon the isolated ileum. The pressure increased slowly and reached a plateau at higher
The molar ratio of Butyl Methacrylate required to produce than control values for 10-15 min. Heart rate decreased at all
a 50% inhibition of the acetylcholine and barium chloride re- dose levels compared to control values, the percent change
sponses was 15,500 and 51.0, respectively. These data suggest ranged from 8-17%. Respiratory rate increased at all dose lev-
that the origin of the inhibitory effects of Butyl Methacrylate els of Butyl Methacrylate, the percent change ranged from
upon isolated guinea pig ileum are myogenic. These effects 162–356%.
could be terminated by washing with fresh Tyrode’s solution Dose-related cardiac responses included bradycardia, a re-
(Mir et al. 1973b). duced rate of impulse transmission through the A-V node, and
possible acute cardiac ischemia. Higher doses produced prema-
ture ventricular contractions and incomplete A-V block (Mir
Acute Ethylene Glycol Dimethacrylate Toxicity et al. 1974).
oral
Lewis (2000) listed the Ethylene Glycol Dimethacrylate oral Dermal
LD50 in the rat as 3300 mg/kg and the oral LD50 in the mouse HEMA was reported to cause slight irritation to rabbits. No
as 2000 mg/kg. No details were available. other information was available (Gould 1987).
74 COSMETIC INGREDIENT REVIEW

Acute Hydroxypropyl Methacrylate Toxicity 1.4 g/kg. Isobutyl Methacrylate was considered as slightly more
Oral toxic than the n-butyl isomer.
Hazelton Laboratories (1961) assessed the acute oral toxi-
city of Hydroxypropyl Methacrylate in rats. Rats (5 per dose Intravenous
group) were administered 100, 316, 1000, 3160, 10,000 and Mir et al. (1974) reported a study in which male mongrel dogs
31,600 mg/kg Hydroxypropyl Methacrylate via stomach tube. (9–12 kg; 3 dogs/group) were anesthetized and given 0.0167 ml
Toxic effects were observed at 1, 4, and 24 hours and once daily (104 × 10−6 M), 0.0334 ml (208 × 10−6 M), 0.0668 ml (416 ×
for seven days after dosing. 10−6 M), or 0.1336 ml (832×10−6 M) Isobutyl Methacrylate by
Immediately following dosing, most dose groups showed iv injection. Blood pressure, heart rate, electrocardiogram and
depression, labored respiration, and ataxia. The LD50 was respiration rate were measured.
11,200 mg/kg with confidence limits between 6380 and 19,700 The highest dose was rapidly fatal to the dogs. Following
mg/kg. No rats died in the 100, 316, 1000, 3160 mg/kg dose injection of Isobutyl Methacrylate an abrupt decrease in systemic
groups. Two of five rats died in the 10,000 mg/kg dose group blood pressure (33-60%) occurred which lasted for 2 to 4 min at
within 24 hours. Five of five rats died in the 31,600 mg/kg dose all doses. The pressure increased slowly and reached a plateau at
group within one hour (Hazelton Laboratories 1961). higher than control values for 10 to 15 min. Heart rate decreased
The Ministry of Health and Welfare: Japan (1998) reported at all dose levels compared to control values, the percent change
that the acute oral toxicity of Hydroxy-propyl Methacrylate ranging from 10 to 32%. Respiratory rate increased at all dose
was assessed using groups of 5 male and 5 female rats dosed levels of Isobutyl Methacrylate, the percent change ranged from
with 0, 500, 1000, and 2000 mg/kg/day of Hydroxypropyl 162 to 356%.
Methacrylate by gavage. No animals died. The LD50 was greater Dose-related cardiac responses included bradycardia, a re-
than 2000 mg/kg. High-dose males salivated immediately after duced rate of impulse transmission through the A-V node, and
administration. possible acute cardiac ischemia. Higher doses produced prema-
ture ventricular contractions and incomplete A-V block (Mir
et al. 1974).
Acute Isobutyl Methacrylate Toxicity
Oral Dermal
The oral LD50 of Isobutyl Methacrylate in rats was reported The dermal LD50 of Isobutyl Methacrylate in guinea pigs was
as 6.4 to 12.8 g/kg by Autian (1975). Sandmeyer and Kirwin reported as >20 ml/kg (Autian 1975).
(1981) stated that the oral LD50 for Isobutyl Methacrylate in
rats was >6.3 g/kg. Isobutyl Methacrylate was considered as Inhalation
slightly more toxic than the n-butyl isomer. Greim et al. (1995) Inhalation toxicity in ICR mice was conducted by bubbling
stated that the oral LD50 for Isobutyl Methacrylate in rats was air through Isobutyl Methacrylate at a rate of 2 l/min. Half of
>5000 mg/kg. the mice tested (number not stated) died after exposure to 29.74
The acute ip LD50 for Isobutyl Methacrylate in the mouse mg/L Isobutyl Methacrylate for 289.79 minutes (Lawrence et al.
was 1.340 ml/kg (8.398 moles/106 g) (Mir et al. 1973a). 1974).
The General Electric Company (1975) evaluated the acute
Intraperitoneal inhalation toxicity of Isobutyl Methacrylate by exposing albino
The ip LD50 of Isobutyl Methacrylate in mice was re- rats to atmospheric concentrations of 2 mg/L or 200 mg/L. There
ported as 1.340 ml/kg or 8.398 mole/106 g (Autian 1975; were 5 male and 5 female rats per group and individual rats
Lawrence et al. 1972). Lawrence et al. (1972) stated that acrylate weighed between 200 and 250 grams. Food and water were
monomers were more toxic than the corresponding methacrylate available ad libitum. Rats were exposed to either 2 mg/L or 200
monomers. The lower molecular weight members of the acry- mg/L Isobutyl Methacrylate for 4 hours and then observed for
late/methacrylate series were more toxic than the higher molecu- 14 days thereafter.
lar weight members. Additionally, the straight chain substituent All of the rats exposed to 2.0 mg/L of Isobutyl Methacrylate
was less toxic than the corresponding branched chain, and sim- survived the 14- day observation period. During the exposure pe-
ple aliphatic substituents were less toxic than substituents that riod, two rats had decreased motor activity, eye squint, erythema,
contained hydroxyl or amine functional groups. slight dyspnea, and tonic convulsions. At 24 hours, decreased
Singh et al. (1972) reported a study in which Sprague-Dawley motor activity was observed in several rats but by 48 hours all
rats received a single ip injection of Isobutyl Methacrylate and rats appeared normal. Eight of the ten rats exposed to 200 mg/L
were observed over seven days for mortality. The LD50 for of Isobutyl Methacrylate died. Two male rats died at the end of
Isobutyl Methacrylate was reported as 1.3999 ml/kg (95% con- the exposure period, and within 3 hours following the end of the
fidence limits were 1.1077–1.7693). exposure period, two male and three female rats died. An ad-
Sandmeyer and Kirwin (1981) stated that the ip LD50 for ditional female rat was found dead at 24 hours. The remaining
Isobutyl Methacrylate in mice was 1.19 g/kg and in rats was male and female rats survived the observation period.
 ESTER MONOMERS USED IN NAIL ENHANCEMENT PRODUCTS 75

During the exposure period the following parameters first inhibitory effects of Isobutyl Methacrylate upon isolated guinea
increased then decreased; motor activity, eye squint, erythema, pig ileum are myogenic. These effects could be terminated by
salivation, lacrimation, clear nasal discharge, nasal porphyrin washing with fresh Tyrode’s solution (Mir et al. 1973b).
discharge, tachypnea, both slight and marked dyspnea, ataxia,
tonic convulsions and prostration.
At 24 hours, surviving rats had urine stained abdomens, Acute Lauryl Methacrylate Toxicity
corneal surface drying, hypersensitivity to touch accompanied Oral
by vocalization, marked dyspnea, respiratory congestion, and The Rohm and Haas Co. (1966a) administered a single oral
dehydration. After 5 days, both surviving rats appeared normal. dose of 0.464, 1.0, 2.15, 4.64, 10 or 21.5 ml/kg C12-C18
At necropsy, 1 of 4 males had no gross lesions, 3 of 4 males and 4 Methacrylate monomer solution to male albino Sprague-Dawley
of 4 females had lung congestion, 1 of 4 males had yellow areas rats. Observations were made at one, four, and 24 h and once
on the lung, and 1 of 4 females had a blood clot in the stomach. daily for 14 days upon which all animals were killed. No deaths
Based upon the results, Isobutyl Methacrylate was considered a occurred at any of the dosages tested. No significant signs of
toxic (but not a highly toxic) substance by inhalation exposure toxicity were observed. Necropsy findings were unremarkable.
(General Electric Company 1975).
Intraperitoneal
In vitro The ip LD50 for Lauryl Methacrylate in mice was
Mir et al. (1973a) perfused isolated rabbit hearts in vitro with 24.897 ml/kg or 84.531 moles/106 g (Lawrence et al. 1972;
1:100,000, 1:10,000 or 1:1000 dilutions of Isobutyl Methacry- Autian 1975; Mir et al. 1973a).
late. Isobutyl Methacrylate was tested five times but the number
of hearts used was not available. The procedure used a uniform
Intravenous
hydrostatic pressure that provided a constant perfusion pressure.
Each heart was perfused for a 20 min equilibration period and Mir et al. (1974) tested the effect of 0.1550 ml (418 x 10−6
the test was conducted over the following 90 min. The test solu- M), 0.3100 ml (836 x 10−6 M), 0.6200 ml (1672 x 10−6 M), or
tion was introduced as the perfusate for one minute after cardiac 1.2400 ml (3344 x 10−6 M) Lauryl Methacrylate on respiratory
activity had stabilized and then normal Locke’s solution was and cardiovascular functions in anesthetized dogs as described
perfused to permit recovery of the heart. The effect was consid- earlier for other chemical exposures.
ered irreversible if cardiac activity did not return significantly The highest dose was rapidly fatal to the dogs. Following
to control levels within 30 to 35 min of perfusion with normal injection of Lauryl Methacrylate, at all doses, a decrease in
Locke’s. systemic blood pressure (5-19%) occurred. Heart rate also de-
Isobutyl Methacrylate produced an irreversible effect on the creased at all doses from 2 to 10% of controls. Respiratory rate
isolated heart at only the highest concentration. The lowest con- increased only at the highest dose level of Lauryl Methacry-
centration did not change the cardiac rate per minute, force of late, the percent change was 41. Cardiac responses included the
contraction or coronary flow. The cardiac rate per minute, force following: bradycardia and a marked effect upon ventricular re-
of contraction (g) and coronary flow (ml/min) were significantly polarization, as the dose increased, the T wave was decreased
decreased at all concentrations tested compared to control. The and became inverted or biphasic with a marked increase in the
only exception was that coronary flow was not significantly ST segment; the PR interval was prolonged (Mir et al. 1974).
affected at the lowest and middle concentrations of Isobutyl
Methacrylate solution (Mir et al. 1973a). Inhalation
Mir et al. (1973b) exposed newly isolated guinea pig ileum of The Haskell Laboratory (1993a) exposed male Swiss Webster
either sex to Isobutyl Methacrylate once at dilutions of 1:2000, mice (4/group) to 460, 1500, 2100, 2900 or 3800 ppm Lauryl
1:1000 or 1:500. The number of samples used was not specified. Methacrylate for 30 min in an inhalation chamber. Respiratory
The spontaneous activity of the intestine to Tyrode’s solution rates were recorded every 15 seconds during exposure and the
was recorded and then Isobutyl Methacrylate was added to the 10 min postexposure period.
bath and the response recorded. Respiratory rates gradually declined during each exposure
Isobutyl Methacrylate produced a concentration-dependent to Lauryl Methacrylate, the lowest rates occurred 25–30 min
depressant effect upon spontaneous motility of the isolated into the exposure time. Respiration rates increased slowly when
guinea pig ileum. Additionally, a concentration-dependent an- the exposures were discontinued. Breathing patterns of sensory
tagonism of the neurogenic and myogenic stimulant effects of irritation coincided with decreased respiratory rates. Irritation
acetylcholine (1:10,000,000) and barium chloride (3:100,000) was most severe at the end of the exposure period and a slow
was observed upon the isolated ileum. The molar ratio of onset of abnormal breathing patterns occurred. The RD50 of
Isobutyl Methacrylate required to produce a 50% inhibition of Lauryl Methacrylate was 3900 mg/m3 . Lauryl Methacrylate was
the acetylcholine and barium chloride responses was 14,125 considered a sensory irritant and had a low potential for causing
and 50.0, respectively. These data suggest that the origin of the upper respiratory tract irritation (Haskell Laboratory 1993a).
76 COSMETIC INGREDIENT REVIEW

In vitro the animals that were killed at the end of the observation period
Mir et al. (1973a) tested the effect of Lauryl Methacrylate (Industrial Bio-Test Labs 1973).
on isolated, perfused rabbit hearts in vitro using the same pro- Andrews and Clary (1986) stated that the oral LD50 value of
tocol as described for Butyl Methacrylate. Lauryl Methacrylate Trimethylolpropane Trimethacrylate in the rat was 5.7 ml/kg.
produced a reversible effect at all three concentrations tested
(1:100,000, 1:10,000 or 1:1000). Cardiac rate per minute and Dermal
force of contraction were significantly decreased compared to The Industrial Bio-Test Labs (1973) assessed the acute der-
controls at the highest concentration tested, while coronary flow mal toxicity of Trimethylolpropane Trimethacrylate in young
(ml/min) was significantly increased compared to controls at the albino rabbits. Trimethylolpropane Trimethacrylate was ap-
highest concentration tested. Force of contraction (g) was signif- plied to the shaved backs of four rabbits (2 male, 2 female)
icantly decreased compared to controls at the middle concentra- at a dose level of 3,000 mg/kg for 24 hours under an oc-
tion tested. Of the 12 methacrylates tested, Lauryl Methacrylate cluded patch. Observations were noted for up to 14 days post-
had the least depressant effect upon the isolated rabbit heart at application.
the concentrations tested. No rabbits died during the study. Slight edema and pale red
erythema was noted at the test site at 24 hours. At 14 days,
Acute PEG-4 Dimethacrylate Toxicity slight to mild desquamation was noted. The dermal LD50 value
Oral of Trimethylol propane Trimethacrylate in the rabbit was >3,000
The oral LD50 value of PEG-4 Dimethacrylate in the rat was mg/kg (Industrial Bio-Test Labs 1973).
>5000 mg/kg. No other details were available (Andrews and Andrews and Clary (1986) stated that the dermal LD50
Clary 1986). value of Trimethylolpropane Trimethacrylate in the rab-
bit was 16 ml/kg and Gould (1987) stated that Trimethy-
Dermal lolpropane Trimethacrylate caused moderate irritation to
The dermal LD50 value of PEG-4 Dimethacrylate in the rat rabbits.
was >3 g/kg. No other details were available (Andrews and
Clary 1986). Intraperitoneal
Biodynamics (1981) reported a study in which rats were in-
Acute Tetraethylene Glycol Dimethacrylate Dermal jected ip with Trimethylolpropane Trimethacrylate. Rats (5 male
Toxicity and 5 female per dose group) were injected with 2000, 3500,
Tetraethylene Glycol Dimethacrylate was reported to cause 5000, or 8000 mg/kg Trimethylolpropane Trimethacrylate (in
mild irritation to rabbits. No other information was available corn oil). Animals were observed at 1, 2, and 4 hours, and daily
(Gould 1987). for 14 days after dosing.
No rats died in the group dosed with 2000 mg/kg Trimethy-
Acute Triethylene Glycol Dimethacrylate Oal Toxicity lolpropane Trimethacrylate. In the 3500 mg/kg dose group, 4
Lewis (2000) stated that the Triethylene Glycol Dimethacry- of 5 males died on days 5 to 7; no females died. In the 5000
late oral LD50 values in mice and rats were reported as 10,750 mg/kg dose group, 4 of 5 males and 5 of 5 females died on days
and 10,837 mg/kg, respectively. 2 to 9. In the 8000 mg/kg dose group, 5 of 5 males and 4 of 5
females died on days 2 to 5. The LD50 in the rat was 3900 mg/kg
Acute Trimethylolpropane Trimethacrylate Toxicity (3100 mg/kg male; 4300 mg/kg female). Tremors, convulsions,
Oral and ataxia were observed at all dose levels. Animals that died
The Industrial Bio-Test Labs (1973) assessed the acute oral had severe weight loss, and surviving animals exhibited weight
toxicity of Trimethylolpropane Trimethacrylate using albino losses up to day 7 after which weight was gained (Biodynamics
rats. Two male and two female rats per dose group were di- 1981)
rectly dosed with Trimethylolpropane Trimethacrylate (10,250, The ip LD50 of Trimethylolpropane Trimethacrylate in mice
15,380, 23,070, or 34,600 mg/kg) into the stomach by a syringe was reported as 2.727 ml/kg or 8.537 moles/106 g (Autian
with a ball-tipped intubating needle. Rats were then observed 1975; Lawrence et al. 1972). Lewis (2000) listed the ip
for 14 days. LD50 of Trimethylolpropane Trimethacrylate in rats as 2889
No rats died in the 10, 230 or 15,380 mg/kg dose groups. mg/kg.
One of 4 rats died in the 23,070 mg/kg dose group at 6 to 22
hours after dosing. In the high-dose group all four rats died Inhalation
between day 1 to 4. The oral LD50 value of Trimethylolpropane In its workplace exposure guide, the American Industrial Hy-
Trimethacrylate in the rat was 25,530 mg/kg. giene Association (1981) stated that none of the “lab animals”
At necropsy the animals had gastroenteritits, hemorrhages in (species not given) exposed for 6 hours to air saturated by sparg-
the stomachs, and pale livers. No gross lesions were noted in ing through Trimethylolpropane Trimethacrylate at 60◦ C died.
 ESTER MONOMERS USED IN NAIL ENHANCEMENT PRODUCTS 77

Short-Term Butyl Methacrylate Toxicity Short-term t-Butyl Methacrylate Toxicity

Oral Oral
Male rats (5/group) were dosed eleven times with 100 or The Ministry of Health and Welfare: Japan (1998) reported
1000 mg/kg Butyl Methacrylate over a 15-day period. The con- the results of a study in which the oral toxicity of t-Butyl
trol group was dosed with water. No abnormalities were ob- Methacrylate was assessed in a 28-day repeat dose toxicity test.
served for the low dose group. The high dose group had slightly Groups of 6 male and 6 female rats were dosed with 0, 20, 100,
decreased weight gain and feed consumption and as inactive af- and 500 mg/kg/day of t-Butyl Methacrylate by gavage. All rats
ter dosing. Clinical chemistry, gross pathology, histopathology, were killed on day 29.
and absolute and relative liver and kidney weights of the treated The NOEL was 20 mg/kg/day in males and females given
groups were comparable to controls (Eastman Kodak Co. 1984). t-Butyl Methacrylate. No deaths occurred throughout the study.
The Ministry of Health and Welfare: Japan (1998) reported There was no effect on food consumption and body weights
a study in which the oral toxicity of Butyl Methacrylate was between controls and treated groups. With blood chemical ex-
assessed as part of a reproductive/developmental toxicity study. amination there was an increase in total cholesterol and total
Groups of 10 male and 10 female rats were dosed with 0, 30, protein in both sexes at the 100 and 500 mg/kg/day dose lev-
100, 300, or 1000 mg/kg/day of Butyl Methacrylate by gavage. els, an increase in albumin in females given 100 mg/kg/day
Males were dosed for 44 days and females were dosed from 14 and both sexes given 500 mg/kg/day, and a decrease in alkaline
days before mating to day 3 of lactation. All male rats were killed phosphatase in males given 100 mg/kg/day and both sexes given
on day 45 and female rats were killed on day 4 of lactation. 500 mg/kg/day.
The NOEL was 30 mg/kg/day in males and 300 mg/kg/day in Urinalysis demonstrated an increase in protein at the highest
females given Butyl Methacrylate. Weight gain depression and a dose in both sexes. Also, at the highest dose level, males had
decrease in food consumption was observed in high dose males an increase in erythrocytes and females had an increase in
and females. In males, absolute and relative weights of the spleen epithelial cells.
were decreased at doses of 100 mg/kg or more, and relative Hypertrophy of the liver in three high-dose males and five
kidney weights were increased at 100 mg/kg or more. Atrophy high-dose females was noted at necropsy. Centrilobular hyper-
of the splenic red pulp was observed at doses of 100 mg/kg or trophy of hepatocytes in four males given 100 mg/kg/day t-Butyl
more in males and 100 mg/kg in females. The kidneys had no Methacrylate and all high-dose animals was noted microscopi-
histopathological abnormalities attributed to Butyl Methacrylate cally (Ministry of Health and Welfare: Japan 1998).
(Ministry of Health and Welfare: Japan 1998).
Short-Term HEMA Toxicity
Inhalation
Oral
The Haskell Laboratories (1977a) exposed ten adult male
The Ministry of Health and Welfare: Japan (1998) reported
ChR-CD rats via inhalation to 1200 ppm (average analyti-
the results of a study in which the oral toxicity of HEMA was
cally determined concentration was 1248 ± 198 ppm) Butyl
assessed (part of a reproductive/developmental toxicity study).
Methacrylate for five days a week, six hours a day for two-
Groups of 12 male and 12 female rats were dosed with 0, 30,
weeks. A group of 10 control rats was also included. Blood and
100, 300, or 1000 mg/kg/day of HEMA by oral gavage. Males
urine samples were taken from all animals on the last expo-
were dosed for 49 days and females were dosed from 14 days
sure day and 5 rats/group were necropsied. The remaining five
before mating to day 3 of lactation. All male rats were killed on
rats/group underwent a two-week recovery period.
day 50 and female rats were killed on day 4 of lactation.
No abnormal weight gains or clinical observations were noted
The NOEL was considered to be less than 30 mg/kg/day
in treated rats compared to controls. At the end of the two-week
in males and 30 mg/kg/day in females given HEMA. Blood
exposure period, the treated rats had moderately higher red blood
urea nitrogen concentration was elevated or high at concentra-
cell counts and hemoglobin and hematocrit values than the con-
tions of 30 mg/kg/day or more. One high-dose male and five
trol rats; however, these values returned to control levels after
high-dose females died (Ministry of Health and Welfare: Japan
the two-week recovery period. No significant differences were
1998).
observed between test and control groups with respect to other
Schneiderka et al. (1996) conducted a study in which fe-
hematological, blood chemical or urine analytical measurements
male Wistar rats were given a subacute intramuscular injec-
at the end of either sampling period. No compound-related ef-
tions of HEMA. The three dose groups were 2.164, 2.296, and
fects were observed grossly or microscopically (Haskell Labo-
2.471 ml/kg which were the LD0.02 , LD0.2 , and the LD 2.0 , re-
ratories 1977a).
spectively. There were six rats per control group and a dose
Greim et al. (1995) reported the results of a 28-day inhala-
group at each time interval. Blood was collected and rats were
tion study of Butyl Methacrylate in rats. The main effect was
killed in 5 intervals on days 1, 5, 10, 15, and 20. Hematologic
irritation of the upper airway; the NOEL was 1801 mg/m3 . No
parameters and the dynamics of some clinical chemical analytes
other information was available.
were monitored.
78 COSMETIC INGREDIENT REVIEW

Hematologic parameters were not very sensitive to HEMA were comparable between the control group and the Trimethy-
at the doses tested. There were no significant differences in the lolpropane Trimethacrylate-treated groups data (Hazelton Lab-
means of corpuscule counts, in the means of hemoglobin and oratories 1982).
fibrinogen concentrations and in the mean coagulation times
between HEMA and the controls. There were no significant Dermal
changes in sodium and total calcium concentrations, however In a workplace exposure guide, the American Industrial Hy-
there were elevated concentrations of potassium at the end of giene Association (1981) stated that rabbits (number not given)
the experiment. Chloride and creatine concentrations were de- had 300 mg/kg undiluted Trimethylolpropane Trimethacrylate
creased as well (Schneiderka et al. 1996). applied to the skin 5 days per week for 2 weeks. Skin corrosion
was noted but no organ effects were noted. No other details were
available.
Short-Term Lauryl Methacrylate Toxicity
Inhalation
Subchronic Lauryl Methacrylate Toxicity
Gage (1970) used unspecified concentrations of Lauryl
Oral
Methacrylate to produce acute effects in Alderley Park rats after
Rohm and Haas Co. (1966b) conducted a study in which adult
short exposures. Thereafter, the exposure period was extended
purebred Beagles (3/sex/group) were dosed orally by capsule
and the concentration decreased until the animals survived 6 h
daily for 13 weeks with 0.2, 0.6, or 2.0 g/kg/day of a test material
exposures, 5 days/week for four weeks. Urine was collected
that contained C12 to C18 Methacrylate monomers. A control
overnight after the last day of exposure and on the following
group was also included. Hematology, biochemistry and urine
day the rats were killed. The experiments were performed until
analyses were performed initially and at one and three months.
a concentration was reached that produced no toxic effects. At
Terminal sacrifice occurred at 13 weeks.
two month intervals, control rats were maintained in the chamber
Only at the highest dose were compound effects observed in
consistent with the exposure period. Rats (2/sex) were exposed
the form of emesis, diarrhea, mucoid feces or salivation. Some
to a saturated solution of Lauryl Methacrylate for twenty 6 h
weight loss was also observed in this group. Observations and
exposure periods (exact dose not available). No toxic signs were
body weights were normal for all other dose groups and the con-
observed and necropsy was normal.
trol. Hematology, biochemistry and urine analyses were compa-
rable between the control and treated groups. On gross exami-
Short-Term Trimethylolpropane Trimethacrylate Toxicity nation there were no compound-related tissue alterations among
Oral test groups. No significant organ weight changes were observed,
Hazelton Laboratories (1982) evaluated Trimethylolpropane although mean liver/body weight ratios for male and female high
Trimethacrylate for tolerance in pregnant rats to establish dose dose dogs and mean kidney/body weight ratios for three female
levels for a teratology study. Pregnant rats (6 per dose level) high dose dogs were slightly increased compared to controls.
were given 500, 2500, or 5000 mg/kg/day of Trimethylolpropane Microscopic examination of tissue sections from control and
Trimethacrylate by intubation from days 6 to 15 of gestation. Six treated dogs revealed compound-related cytologic alterations in
rats received corn oil only and served as the control group. Rats the livers of two males and two females in the high dose group.
were evaluated for mortality, clinical signs, body weights, food Slight to moderate paleness and vacuolation of the cytoplasm
consumption, water consumption, gross pathology, and ovarian and pigmentation of small yellowish granules were observed in
and uterine weights. some of the hepatic cells. Necrosis was not apparent and the
Trimethylolpropane Trimethacrylate-related effects were ob- changes appeared reversible (Rohm and Haas Co. 1966b).
served. Five of six rats died in the 5000 mg/kg/day group, but Rohm and Haas Co. (1966c) fed albino rats a diet containing
no rats in any other dose groups died. The following clinical C12-C18 Methacrylate monomer (10/sex/group) at concentra-
observations were noted in the high-dose group: bloody crust (5 tions of 5000, 15,000 and 50,000 ppm for thirteen weeks. Control
animals), wheezing (1 animal), labored respiration (1 animal), animals were fed a basal diet. Hematology, clinical chemistry
urine stains (6 animals), rough haircoat (2 animals), stains on and urine analyses were performed on five animals of each sex
fur (1 animal), soft feces (2 animals), hunched (2 animals), thin from each group at one and three months. The study was termi-
(6 animals), and depressed (1 animal). The mean weights and nated at 13 weeks.
weight changes were decreased in high-dose rats from days 9 to The appearance and behavior of test rats was compara-
15. Mean food consumption was increased in high and low-dose ble to controls. Growth and food consumption for the high
rats from days 6 to 14, but these findings were not considered dose females and males were significantly lower compared to
significant. the controls, while that of the low and mid-dose animals were
All six rats at 5000 mg/kg/day Trimethylolpropane comparable to the controls. No deaths occurred in any of the
Trimethacrylate had gross lesions in the lungs (dark red areas), groups. Hematological, biochemical and urine analyses were
liver (white or tan areas), kidneys (pelvis dilated), and stom- comparable between test and control groups. No gross changes
ach (smooth, thin areas). The mean ovarian and uterine weights attributable to ingestion of the test material were observed.
 ESTER MONOMERS USED IN NAIL ENHANCEMENT PRODUCTS 79

Terminal body weights for the high dose group were signifi- Moderate to severe corneal opacity, moderate to mild iritis
cantly less than the controls. Liver weight was significantly less and moderate to severe conjunctival irritation was produced in
for the high dose males compared to the controls; however, the the unwashed treated eye. The washed treated eye had moderate
liver/body weight ratio for females was significantly increased corneal opacity, moderate to mild iritis and moderate conjunc-
compared to controls. The kidney/body weight ratio of the mid- tival irritation. The washed treated eye was normal at 21 days,
and high-dose group females was significantly increased com- while the unwashed treated eye had a small area of mild opacity
pared to controls. The higher organ/body weight ratios recorded at 21 days.
for the high-dose group may have reflected the effect of reduced A possible systemic effect of pupil constriction was also noted
food consumption and decreased body weight gain. The differ- in both eyes. This material was classified as a moderate eye
ences were not supported by gross or microscopic examination irritant capable of producing permanent mild corneal opacity (E
of pertinent tissues. Microscopic examination of tissues from I Dupont de Nemours & Co. Inc. 1976).
male and female rats did not reveal any compound-related le- The Haskell Laboratories (1977b) reported the results of a
sions (Rohm and Haas Co. 1966c). study in which Butyl Methacrylate or Isobutyl Methacrylate
(0.1 ml) was placed into the right conjunctival sac of each of
Chronic Methyl Methacrylate Toxicity two rabbits as an undiluted test material. Twenty seconds after
A study on the chronic inhalation toxicity and oncogenicity contact, the treated eye of one rabbit was washed with tap wa-
of methyl methacrylate in rats and hamsters by Lomax et al. ter for one minute. The treated eye of the other rabbit was not
(1997) was available. For 24 months male and female Fis- washed. Observations were recorded at 1 and 4 hrs and on days
cher 344 rats (70 males and 70 females/group) were exposed 1, 2, 3, and 7 following treatment.
to methyl methacrylate monomer vapors at 0, 25, 100, and 400 Effects on the cornea or iris were not observed for either
ppm (6 h/day, 5 days/week) and for 18 months. Female Lakeview treatment. The washed treated eye had mild redness and slight
golden hamsters (53–56 males and 56–59 females/group) were swelling for 1–4 h. The unwashed treated eye had mild red-
exposed to similar concentrations. Animals were monitored for ness and slight swelling for 1 h to 1 day. A mild discharge was
clinical signs, body weights, hematology, clinical chemistry (rats observed at 4 h (Haskell Laboratories 1977b).
only), and urinalyses (rats only). Ten rats per sex/per group were The British Petroleum Company (1981) assessed the eye ir-
killed after weeks 13 and 52, all surviving rats were killed during ritancy of HEMA using three albino rabbits. Approximately 0.1
weeks 104 to 106. All surviving hamsters were killed at week 78. ml of neat HEMA was applied to one eye of each rabbit. Ocu-
Mortality, hematology, clinical chemistry, and urinalyses lar irritation was scored at 3 hours, and 1, 2, 3, 7, and 15 days
were not affected by methyl methacrylate exposure in rats. Male post-instillation.
rat body weights were not affected by methyl methacrylate; HEMA caused immediate eye discomfort and resulted in
however, female rats exposed to 400 ppm weighed less than large areas of corneal ulceration. Redness, discharge, and
controls after 52 weeks. The nasal cavity was the target organ chemosis were also observed but most irritant effects were no
for chronic toxicity in male and female rats exposed to 100 longer present on day 15. The researchers concluded that HEMA
or 400 ppm where microscopic changes occurred primarily in was severely irritating to the rabbit eye and may cause perma-
olfactory epithelium lining the dorsal meatus and consisted of nent injury, especially if not washed quickly from the eye (British
degeneration of neuroepithelium, basal cell hyperplasia and Petroleum Company 1981).
atrophy of Bowman’s glands. Rohm and Haas (1981) applied HEMA CD (88% HEMA,
In hamsters, mortality, hematology, clinical chemistry, and 1.5% Ethylene Glycol Dimethacrylate) to the conjunctival sac
urinalyses were not affected by methyl methacrylate exposure. of three New Zealand white rabbits. Rabbit eyes were unwashed
Male and female hamsters exposed to 400 ppm methyl methacry- after 0.1 ml of HEMA CD was introduced. HEMA CD was
late weighed 9 to 12% less than controls after 48 weeks. No classified as corrosive to rabbit eyes.
microscopic changes were observed in the nasal cavity of the Andrews and Clary (1986) stated that PEG-4 Dimethacrylate
hamsters. Chronic exposure to methyl methacrylate vapor did and Trimethylolpropane Trimethacrylate were “virtually nonir-
not cause tumors in hamsters or rats (Lomax et al. 1997). ritating” when instilled in rabbit eyes in the Draize test. No other
information was available.
Ocular Irritation The Industrial Bio-Test Labs (1973) assessed the eye ir-
E I Dupont de Nemours & Co. Inc. (1976) placed a ma- ritation caused by Trimethylolpropane Trimethacrylate using
terial composed of 71% Butyl Methacrylate/2-isocyanatoethyl the Draize test. Undiluted Trimethylolpropane Trimethacrylate
methacrylate (48/52) and 29% ethyl acetate (0.1 ml undiluted) (1 ml) was instilled into the conjunctival sac of one eye in 6
into the right conjunctival sac of each of two albino rabbits. rabbits. The irritation of the cornea, iris, and conjunctiva were
The amount of residual monomer reported was ∼0.3% DWB to scored (maximum = 110).
MRB. Observations were recorded at 1 and 4 hrs and on days 1, The average irritation scores at 1 minute, 1 hour, and
2, 3, and 7 following treatment, with additional observations on 24 hours were 17.0, 8.1, and 0.0, respectively. Most irritation was
days 14 and 21. noted in the conjunctiva. Trimethylolpropane Trimethacrylate
80 COSMETIC INGREDIENT REVIEW

was considered minimally irritating (Industrial Bio-Test Labs, pigs resulted in moderate irritation after ten applications using
1973). a drop-on technique. Percutaneous absorption was not evident.
No additional information was available.
Dermal Irritation Andrews and Clary (1986) reported that PEG-4 Dimethacry-
The Haskell Laboratories (1969) evaluated the irritancy of late was a slight irritant to rabbits at 24 and 72 hours after a
HEMA and Triethylene Glycol Dimethacrylate using male al- single exposure, and that Trimethylolpropane Trimethacrylate
bino guinea pigs. Each compound was tested on 15 animals. was a slight irritant to rabbits 24 hours after a single exposure.
Primary irritation was evaluated by applying 0.05 ml of HEMA When rabbits were exposed to Trimethylolpropane
(10 or 25%) or Triethylene Glycol Dimethacrylate (2, 5 or Trimethacrylate 5 days a week for 2 weeks, only slight irritation
10%) in a 1:1 acetone dioxane dilution to intact shaved skin for was noted after 2 weeks. No systemic effects were present
24 hours. (Andrews and Clary 1986).
No guinea pigs reacted to 10% HEMA. Three guinea pigs had Katusno et al. (1992) examined the dermal irritation of
mild erythema from 25% HEMA. One guinea pig had mild ery- HEMA in four male Hartley guinea pigs using the primary cuta-
thema from 2% Triethylene Glycol Dimethacrylate. Two guinea neous irritability test. An aqueous solution of 24% methacrylic
pigs had mild erythema when exposed to 5% Triethylene Gly- acid and saline were used as controls. Fifty μl of an aqueous
col Dimethacrylate and 4 guinea pigs had mild erythema from solution of 35% HEMA was applied to the shaved dorsal skin
10% Triethylene Glycol Dimethacrylate. Both HEMA and Tri- every 8 hours on days 1-18, and days 25–32.
ethylene Glycol Dimethacrylate were considered not irritating On the 18th day of application, the first recognizable inflam-
(Haskell Laboratories 1969). matory reaction (slight redness) was noted. On day 25, no re-
The Industrial Bio-Test Labs (1973) assessed the irritation action was visible and there was no reaction on day 32. In the
capacity of Trimethylolpropane Trimethacrylate using six albino methacrylic acid group, there was eschar formation by day 18,
guinea pigs. Trimethylolpropane Trimethacrylate (0.5 ml) was and again on day 32. The authors suggested the results of the
applied to two test sites (abraded and intact) for 24 hours. The primary cutaneous irritability test indicated a possible delayed
sites were examined and scored at 24 and 72 hours. At abraded allergic reaction (Katusno et al. 1992).
skin sites, 3 of 6 rabbits had slight erythema, and at intact skin The local irritability of HEMA was tested in guinea pigs
sites, 3 of 6 rabbits had slight erythema when scored at 24 hours. by intracutaneous injection (0.2 ml). Observations were noted
No reactions were visible at 72 hours. The primary irritation 2 hours and 7 days post-injection. Methacrylic acid and saline
score was 0.2. were used as controls. After 2 hours, HEMA caused redness and
In its workplace exposure guide, the American Industrial vesicles (an irritability score of three). After 7 days, HEMA and
Hygiene Association (1981) stated that Trimethylolpropane methacrylic acid solutions formed eschars (an irritability score
Trimethacrylate was minimally irritating to the rabbit skin. of four). HEMA and methacrylic acid were considered strongly
The British Petroleum Company (1981) evaluated the pri- irritating (Katusno et al. 1992).
mary skin irritation of HEMA (from 3 different suppliers) and Rhône-Poulenc Inc. (1992) assessed the dermal irritation of
Hydroxypropyl Methacrylate in albino rabbits (4–6 per dose Sipomer Hem-HP-T (>90% HEMA, < 5% methacrylic acid,
group). Aliquots (0.25 ml) were applied to abraded and non- 1% water) using 6 rabbits. The test material (0.10 ml) was ap-
abraded shaved dorsal skin and covered for 24 hours with an plied under a patch on the trunk of each animal for 4 hours.
occlusive patch. The test material was then washed off and ap- Corrosion readings were made at 4 and 48 hours. The test mate-
plication sites were scored at 24 and 72 hours after 1st applica- rial was corrosive in 2 of 6 animals after 48 hours. The material
tion. The primary irritation index (PII) of HEMA ranged from was considered corrosive.
0.7 to 1.2 and the PII of Hydroxypropyl Methacrylate was 1.0. Rohm and Haas Co. (1994) reported that six New Zealand
Both HEMA and Hydroxypropyl Methacrylate were classified White rabbits were exposed to undiluted Butyl Methacrylate
as likely to be mild irritants on human skin. (0.5 ml) for one and four hour periods. The hair around the
The Rohm and Haas Co. (1981) conducted an acute range entire trunk between the flank and shoulders was shaved 24 h
finding study to assess skin irritation in New Zealand White prior to dosing. Butyl Methacrylate was applied under semi-
rabbits from exposure to HEMA CD (88% HEMA, 1.5% Ethy- occluded conditions to the right side of the animal for the 4
lene Glycol Dimethacrylate). Six rabbits (three intact skin, three h exposure period. Approximately 3 h into the 4 h exposure
abraded) were exposed to 0.5 ml of HEMA CD under a 24-hour a second application was performed to the left side of the an-
patch and irritation was scored at 24 hours, 72 hours, and 7 days. imal for the 1 h exposure. This site was occluded using the
The PII score at 24 and 72 hours (abraded skin) was 1.3. The same procedure as in the 4 h exposure. Observations were per-
PII score at 24 and 72 hours (intact skin) was approximately formed at 1, 24, 48 and 72 h and 7, 14 and 21 days after patch
0.08. HEMA CD was considered slightly irritating (Rohm and removal.
Haas 1981). No mortality, clinical signs or corrosive effects were observed
Eastman Kodak Co. (1984) reported that repeated applica- during either exposure period. The PII for the 4-hour exposures,
tion of Butyl Methacrylate to the clipped backs of five guinea based on the skin irritation observations up to 72 hours, was 5.6.
 ESTER MONOMERS USED IN NAIL ENHANCEMENT PRODUCTS 81

All rabbits in the four-hour exposure period had well-defined to three or higher was considered positive/total number of animals
moderate-to-severe erythema through day 7 and by day 14 these used) for the 24 h reading was 0. However, at 48 h the AII
effects had diminished to slight or no erythema. Edema was was 10 for both 0.01 and 0.1 μl challenge doses. The AII of
present by 24 h, but at day 7 and 14 this effect was almost gone. skin reactions at 48 h after topical challenge with 10% Butyl
No erythema or edema was present on day 21. Other skin effects Methacrylate in olive oil was 58. A second group of animals
included thickening and cracking of the application perimeter, was immunized with 0.0151 ml Butyl Methacrylate in olive oil
desiccation and skin sloughing of the application area. and challenged on day 95 with 5% Butyl Methacrylate in olive
At the one-hour exposure site, well-defined moderate-to- oil. The AII of skin reactions at 48 h was 70.
severe erythema was observed through day 7 in most rabbits, Guinea pigs immunized with Butyl Methacrylate were chal-
but these effects had diminished to well-defined or no erythema lenged for the third time after immunization was complete with
by day 14. Very slight to moderate edema was observed in most 0.4 and 5% Butyl Methacrylate in olive oil on day 122. The AII
rabbits through 24 h. By 48 and 72 h very slight to slight edema for skin reactions 72 h after topical challenge was 93 for both
was noted in 4/6 rabbits. No edema or erythema was observed challenge concentrations.
by day 7 and 21, respectively. Other skin effects included skin Some animals were tested for cross sensitivity on the second
sloughing at the application site perimeter and desiccation of the or fourth challenge cycle. Twelve hours after exposure positive
application area (Rohm and Haas Co. 1994). skin reactions were observed for methyl and ethyl methacry-
Lewis (2000) stated that Trimethylolpropane Trimethacrylate late. The investigators stated that Butyl Methacrylate was a very
caused mild irritation effects at a dose of 500 mg on rabbit skin. strong sensitizer (Chung and Giles 1977).
No other details were available.
HEMA
Dermal Sensitization The British Petroleum Company (1981) evaluated the sen-
Butyl Methacrylate sitization potential of HEMA in guinea pigs. Two weeks after
Lawrence et al. (1974) reported that Butyl Methacrylate was topical induction, the guinea pigs were challenged at 10 and
non-sensitizing in a guinea pig maximization test (GPMT). No 25% concentrations. One week after the first challenge, the test
additional information was available. and control HEMA groups were re-challenged with 5% HEMA
Chung and Giles (1977) immunized male Hartley albino (from three different suppliers). Skin reactions were evaluated
guinea pigs or male and female English short-hair strain guinea at 48 and 72 hours following the challenge and re-challenge. All
pigs using the following protocol: Freund’s complete adjuvant guinea pigs induced with HEMA were sensitized and reacted
containing heat-killed Mycobacterium butyricum (MB) was di- positively to a challenge using 10% HEMA. Using 5% HEMA,
luted to 250 μg/ml with Freund’s incomplete adjuvant. On day four of the sensitized animals reacted to all three HEMA vari-
0, each guinea pig received 100 μg of MB in the four foot pads eties and two other animals reacted to two varieties of HEMA.
in a volume of 0.4 ml (0.1 ml per foot pad). The researchers concluded that HEMA is an extremely potent
Within four hours after injection of the adjuvant, 0.2 ml of sensitizer.
Butyl Methacrylate (concentrations ranged from 2.5 to 10% v/v) Clemmensen (1985) used the GPMT to study the influence of
in 95% ethanol was topically applied to the clipped nuchal area concentration, vehicle, and cyclophosphamide on sensitization
for the initial induction. This procedure, without adjuvant, was to HEMA. The vehicles used for elicitation were petrolatum,
repeated twice more during the initial 5-day immunization pe- soybean oil, and a mixture of oil and 2-butanone (sbomek). Ten
riod. Control animals received only the adjuvant. to twenty guinea pigs were used per dose group. The follow-
Two groups of animals were challenged at different times. ing materials were used for intradermal induction (day 0): 1%
In the first group, animals were challenged with 2 or 5% Butyl HEMA (in soybean oil), 25% HEMA (in soybean oil), 25%
Methacrylate in ethanol on days 0, 2 and 5. Skin reactions were HEMA (in sbomek), 1% HEMA (aqueous), 10% HEMA (aque-
read 72 h later. These animals received three applications of ous), and 25% HEMA (aqueous). Dermal induction occurred
0.03 ml Butyl Methacrylate in ethanol during the immunization on days 7 and 8 using a 10% sodium lauryl sulfate pretreat-
period. None of the 19 animals reacted positively to the chal- ment and 400 μl of HEMA applied via a 48 hour patch. Chal-
lenge. A second group of animals was challenged with 2 or 5% lenge was performed on day 21 using 25% HEMA (in petro-
Butyl Methacrylate in olive oil on days 60 and 95. The animals latum), 25% HEMA (aqueous), 25% HEMA (sbomek), 25%
received 0.0077 ml of 2 or 5% Butyl Methacrylate in olive oil HEMA (in soybean oil), and 100% HEMA. Effects were scored
once during the immunization period. All nine of these animals at 48 and 72 hours post-challenge. The effect of ip injection of
had positive reactions at 72 h. 200 mg cyclophosphamide/kg body weight 3 days before chal-
The second challenge for a group of animals immunized with lenge was examined.
0.0377 ml Butyl Methacrylate in ethanol occurred on day 60. There were no differences between the vehicles used when
These animals were challenged intradermally (id) with 0.01 or HEMA concentrations were 25% or greater. Response elicita-
0.1 μl/site of Butyl Methacrylate. The average intensity index tion was least effective using 100% HEMA, dilutions were more
(AII) (the sum of the numerical scores of skin reactions, in which effective, in particular with petrolatum. There was no response
82 COSMETIC INGREDIENT REVIEW

to intradermal induction using 1% HEMA (in soybean oil);1% allergic reactions in humans and guinea pigs (Katsuno et al.
HEMA (aqueous) when challenged with 25% HEMA (in petro- 1995).
latum) elicited a response in 4 of 12 guinea pigs, however none
of the other challenge vehicles responded. Hydroxypropyl Methacrylate
The major determining factor for sensitization was the con- Björkner et al. (1980b) assessed the sensitizing capacity
centration used for intradermal injection. Using 10% HEMA of Hydroxypropyl Methacrylate using a GPMT. Groups of
or greater caused a reaction in 2 to 10 guinea pigs out of as ten guinea pigs were used. Sites were pretreated with 10%
many as 12 guinea pigs tested per dose group. Injection of sodium lauryl sulfate in petrolatum. Hydroxypropyl Methacry-
cyclo-phosphamide before challenge increased the number of late (5%) was dissolved in an olive oil and acetone (10:1)
responders and prolonged the period of responsiveness where vehicle to improve dispersion for intradermal induction. For
an erythematous reaction could be elicited. topical induction, Hydroxypropyl Methacrylate was tested at
A delayed hypersensitivity test was performed on BALB/C 25%. Challenge was performed using 2% Hydroxypropyl
mice (4 weeks old) using HEMA. The shaved abdomen of each Methacrylate in petrolatum. Cross-reactivity to HEMA was also
mouse was treated with 0.1 ml of 100% HEMA. A 4% picryl examined.
chloride solution was the positive control. Seven days later 0.03 One of 10 guinea pigs became sensitized to Hydroxypropyl
ml of HEMA was applied to the left pinna. The magnitude of Methacrylate challenge with a mean response of 0.15. The same
inflammation was measured by the swelling of the ear. No mice guinea pig also reacted to HEMA with the same mean response.
had an allergic reaction to HEMA at the concentrations tested The researchers concluded that Hydroxypropyl Methacrylate is
(Katsuno et al. 1995). a weak sensitizer (Björkner et al. 1980b).
In a GPMT, Katsuno et al. (1996) determined the optimum
concentration of HEMA for sensitization and elicitation. Five Isopropylidenediphenyl Bisglycidyl Methacrylate
female Hartley guinea pigs (300–500 g) were used per dose Björkner et al. (1984a) tested the sensitizing capacity of Iso-
group. HEMA was tested as a sensitizer at 0.01, 0.02, 0.1, 0.2, propylidenediphenyl Bisglycidyl Methacrylate using a GPMT.
0.5, 1.0, and 5.0%. HEMA was tested in elicitation at 10, 25, 50, Groups of fifteen guinea pigs were used. Sites were pretreated
and 100%. Induction was performed in two stages. In the first with 10% sodium lauryl sulfate in petrolatum. Isopropyli-
induction, 50 μl of HEMA was injected intradermally. One week denediphenyl Bisglycidyl Methacrylate (10% or 20%) was dis-
later the animals were pretreated with 10% sodium lauryl sulfate solved in an olive oil vehicle to improve dispersion for intrader-
(in petrolatum) for 24 hours. A patch soaked in 200 μl HEMA mal induction. For topical induction, Isopropylidenediphenyl
was placed on the shaved back for 48 hours to induce topical Bisglycidyl Methacrylate was tested at 100%. Challenge was
sensitization. A challenge patch containing 100 μl 0.2% HEMA performed two weeks after topical application using 10% Iso-
was applied for 24 hours on day 22. Challenge concentrations propylidenediphenyl Bisglycidyl Methacrylate (whole product)
were 10, 25, 50, and 100%. in petrolatum. The patch was occluded for 24 hours and the site
Five of five guinea pigs had a positive reaction (strong rube- was read 4 hours after removal.
faction and several vesiculopapules) to 0.2% HEMA at 24 hours Thirteen of 15 guinea pigs became sensitized to Isopropyli-
and 48 hours post patch removal with a mean response of 5.0 denediphenyl Bisglycidyl Methacrylate (whole product) at the
which was the optimum concentration for sensitization. For elic- first and second challenge with a mean response of 1.17. The
itation, only 100% HEMA produced skin reactions. The mean whole product Isopropylidenediphenyl Bisglycidyl Methacry-
responses were 5.0 at 24 hours and 2.4 after 48 hours (Katsuno late could be resolved into three components by HPLC.
et al. 1996). Only fraction 1 (free from linear and branched Isopropyli-
Katsuno et al. (1995) tested HEMA in a GPMT. Fifty μl of denediphenyl Bisglycidyl Methacrylate) caused sensitization in
HEMA was intradermally injected and on day 6 the animals guinea pigs (8 of 15). The authors concluded the allergenic
were pretreated with 10% sodium lauryl sulfate (in petrolatum). potential in fraction 1 may have been epoxy resin MW 340
On day 7, a patch soaked in 0.2 ml HEMA (at 0.2, 1.0, or 5.0%) (Björkner et al. 1984a).
was placed on the shaved back for 48 hours to induce topical
sensitization. A challenge patch containing 100% HEMA was Trimethylolpropane Trimethacrylate
applied for 24 hours on day 21. Industrial Bio-Test Labs (1974) assessed the sensitizing ca-
Six of ten (mean response, 2.4) albino guinea pigs sensitized pacity of Trimethylolpropane Trimethacrylate using ten albino
to HEMA showed a positive reaction at 24 hours and 5 out of guinea pigs. Trimethylolpropane Trimethacrylate (0.5 ml) was
10 (mean response, 2.2) showed a positive reaction at 48 hours. applied undiluted for 5 hours to a Webril pad which was occluded
Strong rubefaction was noted. Cross-reactivity was examined with elastoplast. Two weeks later, a challenge was done using
using methacrylic acid or methyl methacrylate as sensitizers. Trimethylolpropane Trimethacrylate at the insult and virgin site
All 12 guinea pigs tested were negative. The researchers noted for 5 hours. Irritation was scored at 24 and 49 hours. No irrita-
that HEMA produced positive delayed hypersensitivity reac- tion was noted at any time. Trimethylolpropane Trimethacrylate
tions in the guinea pig, but suggested that HEMA has different was not considered a sensitizer.
 ESTER MONOMERS USED IN NAIL ENHANCEMENT PRODUCTS 83

Björkner et al. (1980a) assessed the sensitizing capac- Guinea pigs were induced with an intradermal injection of
ity of Trimethylolpropane Trimethacrylate using a GPMT. 10−1 , 10−2 , or 10−3 M Hexyl Methacrylate and were challenged
Twenty-four guinea pigs were used for each group. Trimethy- 21 days later with 0.1 ml aliquots of 1 M Hexyl Methacrylate
lolpropane Trimethacrylate (1%) was dissolved in an olive applied to the shaved area of the flank.
oil vehicle to improve dispersion for intradermal induction. The challenge phase was performed using the closed patch
For topical induction, Trimethylolpropane Trimethacry- method for 24 h. Dermal response was evaluated 48 h after the
late was tested at 25%. Challenge was performed using challenge application. The vehicle used for the induction phase
0.1% and 0.5% Trimethylol propane Trimethacrylate in was olive oil and for the challenge phase was acetone.
petrolatum. Butyl Methacrylate, Cyclohexyl Methacrylate, and Hexyl
Six of 24 and 16 of 24 guinea pigs became sensitized to Methacrylate were considered moderate sensitizers. Lauryl
0.1% and 0.5% Trimethylolpropane Trimethacrylate, respec- Methacrylate was considered a much stronger sensitizer, in fact it
tively. The controls were negative. One week later, at rechal- was the strongest sensitizer of the 13 methacrylates tested. Alkyl
lenge, 7 of 24 guinea pigs and 10 of 24 control guinea pigs methacrylates with linear side chains having an even number of
reacted to 0.5% Trimethylolpropane Trimethacrylate. The re- carbons were stronger sensitizers than those that had an odd
searchers concluded that Trimethylolpropane Trimethacrylate number of carbons.
is a strong sensitizer (Björkner et al. 1980a). The sensitization rate for Butyl Methacrylate at induction
In its workplace exposure guide, the American Industrial concentrations of 0.1 and 1 M were 0 and 80%, respectively.
Hygiene Association (1981) stated that undiluted Trimethylol- The minimum induction concentration (MIC) was 0.1 M. The
propane Trimethacrylate did not cause sensitization in 10 guinea sensitization rate for Cyclohexyl Methacrylate at induction con-
pigs. No other details were available. centrations of 1, 10−1 and 10−2 M Cyclohexyl Methacrylate was
40.0, 20.0 and 0%, respectively. The MIC was determined as
Urethane Methacrylate 10−1 M. The sensitization rate for Hexyl Methacrylate at induc-
Björkner (1984b) assessed the sensitizing capacity of Ure- tion concentrations of 10−1 , 10−2 , and 10−3 M Hexyl Methacry-
thane Methacrylate using the GPMT. Groups of fifteen guinea late was 33.3, 0, and 0%, respectively. The MIC was determined
pigs were used. The animals were pretreated with 10% sodium as 10−1 M. The sensitization rate for Lauryl Methacrylate at
lauryl sulfate in petrolatum. The purity of the Urethane induction concentrations of 10−4 , 10−5 , 10−6 , 10−7 and 10−8
Methacrylate used in this experiment was 98% according to M Lauryl Methacrylate was 100.0, 100.0, 30.0, 30.0 and 0%,
the manufacturer; this correlated with HPLC analysis. Urethane respectively. The MIC was determined as 10−7 M (Kanazawa
Methacrylate (5%) was dissolved in an olive oil: acetone (10:1) et al. 1999).
vehicle to improve dispersion for intradermal induction. For top-
ical induction, Urethane Methacrylate was tested at 100%. Chal- Cross-Reactions
lenge was performed using 0.015 g of Urethane Methacrylate at The Haskell Laboratory (1969) tested for dermal irritation
a concentration of 1% in petrolatum. and sensitization effects of HEMA and Triethylene Glycol
Only 2 of 15 guinea pigs became sensitized to Urethane Dimethacrylate on guinea pigs. Each compound was tested on
Methacrylate. There was no cross-sensitization with an aromatic 15 male albino guinea pigs. Primary irritation was evaluated
and aliphatic urethane acrylate. Urethane Methacrylate was con- by applying 0.05 ml of HEMA (10, 25, or 98%) or Triethylene
sidered a mild sensitizer (grade II) (Björkner 1984b). Glycol Dimethacrylate (2, 5, 10, and 98%) in a 1:1 acetone diox-
ane dilution to intact shaved skin. Sensitizing treatments were
Multiple Methacrylate Esters done by: nine topical applications of 0.05 ml of 25% HEMA or
Kanazawa et al. (1999) conducted a maximization test of Triethylene Glycol Dimethacrylate (1st application was 5% and
several methacrylates using female Hartley guinea pigs, 5–10 last 8 applications were 10%) to abraded skin of five animals,
animals per group. four 0.1 ml id injections of 1% test material in dimethylphtalate
Guinea pigs were induced with an intradermal injection to a second group of five animals, and two 0.1 ml id injec-
(amount not stated) of 0.1 M or 1 M Butyl Methacrylate and tions of FCA followed 90 minutes later by a 0.1 ml of 1% test
challenged 21 days later with 0.1 ml aliquots of 1 M Butyl material in dimethylphtalate in the third group of five animals.
Methacrylate applied to the shaved area of the flank. After 14 days, the animals were challenged with 0.05 ml of 10%
Guinea pigs were induced with an intradermal injection of Triethylene Glycol Dimethacrylate or 25% HEMA on intact or
10−4 , 10−5 , 10−6 , 10−7 or 10−8 M Lauryl Methacrylate and abraded skin. One week later a second challenge was performed
were challenged 21 days later with 0.1 ml aliquots of 1 M Lauryl using 98% test material.
Methacrylate applied to the shaved area of the flank. At first challenge, 25% HEMA caused no reaction in 14
Guinea pigs were induced with an intradermal injection of guinea pigs and mild erythema in 1 guinea pig (intact skin);
1, 10−1 , or 10−2 M Cyclohexyl Methacrylate and were chal- on abraded skin, 7 guinea pigs had mild erythema and 8 had
lenged 21 days later with 0.1 ml aliquots of 1 M Cyclohexyl no reaction. At second challenge, 98% HEMA caused no re-
Methacrylate applied to the shaved area of the flank. action in 12 guinea pigs, mild erythema in 2 guinea pigs, and
84 COSMETIC INGREDIENT REVIEW

moderate erythema in 1 guinea pig (intact); on abraded skin, 7 None of the guinea pigs had any sensitization effects when
guinea pigs had mild erythema, 5 had moderate erythema, and exposed in the presence of hydroquinone and t-Butyl Methacry-
3 had strong erythema. One of 15 guinea pigs was sensitized to late or HEMA. No guinea pigs had any reaction to concomitant
HEMA. exposure to Butyl Methacrylate and Hydroquinone but 2 of
At first challenge, 10% Triethylene Glycol Dimethacrylate these 8 guinea pigs did react to hydroquinone alone.
caused no reaction in 11 guinea pigs and mild erythema in The authors concluded that these results indicate that Butyl
4 guinea pigs (intact skin); on abraded skin, 12 guinea pigs Methacrylate interferes with the sensitizing potential of hydro-
had mild erythema and 3 had no reaction. At second challenge, quinone. It seemed that the sensitizing potential of any of the
98% Triethylene Glycol Dimethacrylate caused no reaction in 8 methacrylates tested was not influenced by hydroquinone be-
guinea pigs, mild erythema in 6 guinea pigs, and moderate ery- cause 1 of 8 guinea pigs reacted to hydroquinone and Hexyl
thema in 1 guinea pig (intact); on abraded skin, 11 guinea pigs Methacrylate, however this guinea pig had no reaction to hydro-
had no reaction, 2 had mild erythema, and 2 had moderate ery- quinone alone. Hydroquinone was present in all four methacry-
thema. Triethylene Glycol Dimethacrylate sensitized 0–100% lates tested at 0.032 to 0.092 g/l as estimated by HPLC (van der
of animals tested (Haskell Laboratory 1969). Walle et al. 1982).
van der Walle and Bensink (1982) sensitized albino female Parker and Turk (1983) injected the footpads of female
guinea pigs of the Himalayan white spotted outbred strain in the Hartley guinea pigs four times with an emulsion of 2 mg/
Freund’s Complete Adjuvant Test (FCAT) or the GPMT. Two ml of Butyl Methacrylate, Ethylene Glycol Dimethacrylate,
weeks after finishing these tests, one flank of the guinea pig HEMA, Tetrahydrofurfuryl Methacrylate, Triethylene Gly-
was clipped and 6 to 8 acrylic monomers were applied in two col Dimethacrylate, or Trimethylolpropane Trimethacrylate in
rows in a 2 cm2 area. An amount of 0.025 ml of 1 M (or 4 M) ethanol:saline (1:4) in Freund’s complete adjuvant (FCA). An
Butyl Methacrylate, 4 M t-Butyl Methacrylate, 3 M HEMA, or additional 0.1 ml of the emulsion was injected into the nape of the
0.3 M (or 3 M) Hexyl Methacrylate was applied to the flank. The neck. The animals received a total of 1 mg of Butyl Methacrylate,
reactions were read at 24 and 48 h. The procedure was repeated Ethylene Glycol Dimethacrylate, HEMA, Tetrahydrofurfuryl
14 days later using the other flank. The animals were tested six Methacrylate, Triethylene Glycol Dimethacrylate, or Trimethy-
times, alternating the flanks. All animals were finally challenged lolpropane Trimethacrylate. Seven days later, and weekly there-
with the monomer that originally sensitized the animal after after for up to 12 weeks, 0.02 ml of a 2% solution in acetone:olive
the last challenge to detect cross reactions. All monomers were oil (4:1) was applied to the shaved flank of the animals, using a
applied at a non-irritant concentration. different site for each application.
No animals were sensitized to t-Butyl Methacrylate. Four Butyl Methacrylate, Ethylene Glycol Dimethacrylate,
guinea pigs were sensitized to HEMA but the cross reactions to HEMA, Tetrahydrofurfuryl Methacrylate, Triethylene Glycol
Butyl Methacrylate, t-Butyl Methacrylate, and Hexyl Methacry- Dimethacrylate, or Trimethylolpropane Trimethacrylate did not
late were not tested. Three guinea pigs were sensitized to induce contact sensitization using this protocol (Parker and Turk
Hexyl Methacrylate but there were no cross reactions to Butyl 1983).
Methacrylate, t-Butyl Methacrylate, and HEMA. One of two Björkner (1984c) assessed the sensitizing capacity of Ethy-
animals originally sensitized to Butyl Methacrylate had positive lene Glycol Dimethacrylate, Triethylene Glycol Dimethacry-
cross reactions to ethyl, n-butyl, t-butyl, pentyl, neopentyl and late, and PEG-4 Dimethacrylate using the GPMT. Groups of
n-hexyl acrylate and ethyl methacrylate. One out of three and fifteen guinea pigs were used. The animals were pretreated with
2/8 animals had positive cross reactions to Butyl Methacrylate 10% sodium lauryl sulfate in petrolatum prior to topical induc-
when originally sensitized to ethyl and methyl methacrylate, re- tion. Ethylene Glycol Dimethacrylate (5%), Triethylene Glycol
spectively. One out of two animals originally sensitized to Butyl Dimethacrylate (1%), and PEG-4 Dimethacrylate (5%) were
Methacrylate had positive cross reactions with two diacrylates dissolved in an olive oil: acetone (9:1) vehicle to improve disper-
and four dimethacrylates. None of the animals originally sen- sion for intradermal induction. For topical induction, Ethylene
sitized with a diacrylate or dimethacrylate had positive cross Glycol Dimethacrylate, Triethylene Glycol Dimethacrylate,
reactions to Butyl Methacrylate. and PEG-4 Dimethacrylate were tested at 50%. Challenge was
These authors also investigated the role of contact sensiti- performed using 0.015 g of Ethylene Glycol Dimethacrylate,
zation to hydroquinone in the sensitization capacity of Butyl Triethylene Glycol Dimethacrylate, or PEG-4 Dimethacrylate
Methacrylate, t-Butyl Methacrylate, Hexyl Methacrylate, and at a concentration of 1% in petrolatum. The cross-reactivity
HEMA using a GPMT with 8 animals per test group. Guinea patterns for the dimethacrylates were also tested.
pigs were exposed to the methacrylate monomer with and with- Only 1 of 15 guinea pigs became sensitized to Triethylene
out hydroquinone. There was no hydroquinone specified in any Glycol Dimethacrylate. No sensitization was observed in the
of the methacrylates by the manufacturer. An FCAT was used other two Dimethacrylates (Björkner 1984c).
to estimate the sensitizing potential of the methacrylates. Clemmensen (1984) performed a GPMT to assess
The FCAT was negative for Butyl Methacrylate and t-Butyl the cross-reaction patterns induced with Ethylene Glycol
Methacrylate and negative for Hexyl Methacrylate and HEMA. Dimethacrylate, HEMA, Triethylene Glycol Dimethacrylate,
 ESTER MONOMERS USED IN NAIL ENHANCEMENT PRODUCTS 85

and Trimethylolpropane Trimethacrylate. On day 0, guinea pigs Hydroxypropyl Methacrylate had strong cross-reactivity to
received an intradermal injection of 25% HEMA (or 10% Hy- Ethylene Glycol Dimethacrylate but only weak to moderate
droxypropyl Methacrylate, 5% Ethylene Glycol Dimethacry- cross reactivity with HEMA (Rustemeyer et al. 1998).
late, 5% Triethylene Glycol Dimethacrylate , or 5% Trimethy- Rustemeyer et al. (2001) studied the cross-reactivity pat-
lolpropane Trimethacrylate) in the neck region. On day 7, the terns of orally administered methyl methacrylate, HEMA, Hy-
neck area was clipped and 250 mg 10% sodium dodecyl sulfate droxypropyl Methacrylate, and Ethylene Glycol Dimethacry-
in petrolatum was applied uncovered for 24 hours. On day 8, late. During tolerance induction, each experimental group (6
400 μl of 100% HEMA (or 100% Hydroxypropyl Methacrylate, guinea pigs per dose group) received 175 μl of methyl methacry-
100% Ethylene Glycol Dimethacrylate, 100% Triethylene Gly- late, HEMA, Ethylene Glycol Dimethacrylate, DMSO (nega-
col Dimethacrylate , or 100% Trimethylolpropane Trimethacry- tive control) or dinitrochlorobenzene on wafers. Immunization
late) was applied under a patch for 48 hours. Challenge occurred was done on day 0, via intradermal injections of 100 μl of 1.0
on day 21 and scores were read at 48 and 72 hours. M methacrylate solutions in water-FCA emulsion (1:1). Subse-
Animals induced with HEMA had positive cross-reactions quent immunizations were conducted after 1 and/or 2 months.
when challenged with 25% HEMA (7 of 15) and 25% Hy- One week after oral methacrylate administration and 14 days
droxypropyl Methacrylate (5 of 15). Guinea pigs induced with after immunization, open skin tests were carried out on the
Hydroxypropyl Methacrylate had positive cross-reactions when shaved upper flanks by painting 25 μl of solutions containing
challenged with 25% HEMA (2 of 12) and 25% Hydroxypropyl 50% methacrylate (methyl methacrylate, HEMA, or Hydrox-
Methacrylate (3 of 12). ypropyl Methacrylate), 40% DSMO, and 10% ethanol or 0.2%
Animals induced with Ethylene Glycol Dimethacrylate had dinitrochlorobenzene in ethanol. An open skin test was also car-
positive cross reactions when challenged with 100% HEMA ried out on the shaved upper flanks by painting 25 μl of solutions
(1 of 19), 100% Ethylene Glycol Dimethacrylate (10 of 19 and 13 containing 10% Ethylene Glycol Dimethacrylate, 40% DSMO,
of 19), and 100% Triethylene Glycol Dimethacrylate (1 of 19); and 50% ethanol or 0.2% dinitrochlorobenzene in ethanol. Chal-
however, no animals (0 of 19) challenged with 100% Trimethy- lenge reactions were recorded after 6, 24, 48, and 72 hours to
lolpropane Trimethacrylate reacted positively. assess the effect that oral administration of methacrylate had
Animals induced with Triethylene Glycol Dimethacrylate on suppression. T cell transfer experiments were performed to
had positive cross-reactions when challenged with 100% Ethy- assess T cell cross-reactivity and cross-tolerance.
lene Glycol Dimethacrylate (7 of 20), 25% Triethylene Gly- Strong tolerance to the monomethacrylates HEMA and
col Dimethacrylate (9 of 20), and 100% Triethylene Glycol methyl methacrylate could be induced, but not to Ethylene
Dimethacrylate (3 of 20); but no animals reacted positively when Glycol Dimethacrylate. Subsequent sensitization attempts with
challenged with 100% HEMA (0 of 20) or 100% Trimethylol- HEMA, methyl methacrylate, and Ethylene Glycol Dimethacry-
propane Trimethacrylate (0 of 20). late were suppressed 86%, 80%, and 8%, respectively. The in-
Animals induced with Trimethylolpropane Trimethacrylate duced tolerance in methyl methacrylate and HEMA could not
had positive cross-reactions when challenged with 100% Ethy- be broken by repeated sensitization attempts. HEMA-tolerized
lene Glycol Dimethacrylate (2 of 20), 25% Trimethylolpropane guinea pigs have strong cross-tolerances to methyl methacry-
Trimethacrylate (17 of 20), and 100% Trimethylol propane late and Hydroxypropyl Methacrylate (suppression of 56 and
Trimethacrylate (13 of 20); however, none of 20 animals reacted 75%, respectively). Moreover, sensitization with Ethylene Gly-
with 100% HEMA or 100% Triethylene Glycol Dimethacrylate col Dimethacrylate in HEMA-tolerized guinea pigs was pre-
(Clemmensen 1984). vented in 77% of animals tested.
Rustemeyer et al. (1998) studied the cross-reactivity patterns In T cell transfer experiments, splenic- or lymph node-derived
of contact sensitizing-methacrylates using a guinea pig model to T cells of HEMA-tolerant animals were transferred into differ-
assess the sensitizing capacity of methyl methacrylate, HEMA, ent groups of naive recipients. Strong adaptive tolerance was
Hydroxypropyl Methacrylate, and Ethylene Glycol Dimethacry- observed in 90% and 100% of guinea pigs with transferred
late. Guinea pigs were immunized by iv injections of 300 μl of splenic-derived and lymph node-derived T cells, respectively
1.0 M methacrylate solutions in FCA. After 14 days, open skin (Rustemeyer 2001).
tests were performed using 50% HEMA, 50% Hydroxypropyl
Methacrylate, or 10% Ethylene Glycol Dimethacrylate solutions REPRODUCTIVE AND DEVELOPMENTAL EFFECTS
in 40% DMSO in ethanol. Cross-reactivities were investigated
14 days later by skin testing with all four methacrylates. Butyl Methacrylate
Strongly positive responses were induced in most guinea Oral
pigs tested. Sixteen of 18 guinea pigs reacted to HEMA, 15 of The Ministry of Health and Welfare: Japan (1998) reported
16 reacted to Hydroxypropyl Methacrylate, and 11 of 11 reacted the results of a study in which the reproductive/developmental
to Ethylene Glycol Dimethacrylate. HEMA sensitization led toxicity of Butyl Methacrylate was assessed. Groups of 10
to strong cross-reactions to all other methacrylates, while male and 10 female rats were dosed with 0, 30, 100, 300, and
Ethylene Glycol Dimethacrylate had weak cross-reactivity. 1000 mg/kg/day of Butyl Methacrylate by gavage. Males were
86 COSMETIC INGREDIENT REVIEW

dosed for 44 days and females were dosed from 14 days before Butyl Methacrylate was also associated with an increased
mating to day 3 of lactation. All male rats were killed on day 45 death rate of rat offspring during the lactation period, a delay in
and female rats were killed on day 4 of lactation. increase in body weight, a breakdown in functional state of the
The NOAEL was 1000 mg/kg/day in parental males and central nervous system and a suppression of redox processes.
300 mg/kg/day in parental females given Butyl Methacrylate. The teratogenic effects manifested in the offspring were ob-
The number of corpora lutea and implantations were decreased served in the absence of toxic effects observed in the dams. The
in the parental females. Butyl Methacrylate showed no effects development of fetuses with vascular pathology was attributed
on any reproductive parameters of the parental males or devel- to necrosis of the placenta which may have caused a break-
opmental parameters of the offspring (Ministry of Health and down in the uterus-placenta blood circulation. Females in test
Welfare: Japan 1998). groups had uterine bleeding, premature births, stillbirths and a
decreased number of live fetuses. The investigators stated that
Parenteral on the basis of the results obtained, the abnormalities of fetal
Singh et al. (1972) injected pregnant Sprague-Dawley rats development observed might have been due to intrauterine hy-
(5/group) ip with one-tenth, one-fifth or one-third the LD50 poxia. The threshold concentration of Butyl Methacrylate was
of Butyl Methacrylate (LD50 = 2.3039 ml/kg) or Isobutyl determined to be 0.1 mg/m3 (Farmakovskaya and Tikhomirov
Methacrylate (LD50 = 1.3999 ml/kg) determined in a previ- 1993).
ous study. Rats received a single injection on days 5, 10, and 15 Saillenfait et al. (1999) exposed pregnant Sprague-Dawley
of gestation. The doses injected for the treatment groups were rats (22–25/group) to 100, 300, 600 or 1200 ppm Butyl
0.7680, 0.4608 and 0.2304 ml/kg of Butyl Methacrylate and Methacrylate via inhalation 6 h/day on days 6–20 of gestation.
0.4666, 0.2799, and 0.1400 ml/kg of Isobutyl Methacrylate for Day 0 of gestation was the day vaginal smears were confirmed
the high, middle and low dose groups, respectively. An untreated sperm-positive. Control animals were exposed concurrently to
group and separate groups dosed with 0.8222 ml/kg cottonseed filtered room air in a chamber identical to the treatment groups.
oil, distilled water and normal saline were maintained as con- Dosing occurred in 200 L glass/stainless steel inhalation cham-
trols. On day 20 of gestation the rats were killed. bers with an adjustable laminar air flow of 6–20 m3 /h. Food and
The number of corpora lutea and dead fetuses for the treated water were withheld during exposures. Concentrations of Butyl
groups (Butyl Methacrylate and Isobutyl Methacrylate) did not Methacrylate were monitored continuously with a GC equipped
differ significantly from the control groups. A decreased number with a flame ionization detector. Food consumption was mea-
of live fetuses and a significantly increased number of resorp- sured for the gestation day intervals 6–13 and 13–21. Maternal
tions were observed in the high dose group of Butyl Methacry- body weight was recorded on gestation days 0, 6, 13 and 21 and
late compared to controls. A slightly decreased number of live females were killed on day 21.
fetuses and slightly increased number of resorptions were ob- All animals survived the exposure period. Significantly de-
served in the high dose group of Isobutyl Methacrylate compared creased maternal body weight gain during gestation days 6–13
to controls. was observed at concentrations of 300 ppm or higher. The high-
The mean weight of the fetuses in the treated groups (Butyl est concentration group also had significantly decreased body
Methacrylate and Isobutyl Methacrylate) differed significantly weight gain during gestation days 6–21. Absolute weight gain
from controls. Gross abnormalities (most commonly heman- was significantly decreased at 1200 ppm. Food consumption
giomas on various parts of the body and to a lesser degree twisted was significantly decreased during gestation days 6–13 at 300
hind legs) were significantly increased in all treatment groups and 1200 ppm and at the highest concentration during gestation
compared to all control groups. Skeletal abnormalities were not days 6–21. No significant changes in the number of implanta-
significantly different between the treated and control groups tions, live fetuses, incidence of non-live implants or resorptions
(Singh et al. 1972). or in fetal sex ratios were observed across the groups.
Fetal body weights were significantly decreased at the high-
Inhalation est concentration; however, only female fetuses in the 600 ppm
Farmakovskaya and Tikhomirov (1993) exposed pregnant group had significantly decreased body weights. Visceral mal-
white rats via continuous inhalation to Butyl Methacrylate at formations occurred in low frequency and were distributed
concentrations of 0.01, 0.1, 0.3 and 4.0 mg/m3 . In this prelimi- across both treatment and control groups. No significant dif-
nary report of their work, the authors provided no further details. ferences were observed between the control and treated groups
Butyl Methacrylate caused embryotoxic and teratogenic effects with respect to incidences of individual or total external and
in the form of increased intrauterine death compared to the con- visceral variations or of individual skeletal variations.
trol group, increased vascular pathology in a number of fetuses At the highest concentration of Butyl Methacrylate, statis-
and increased frequency of functional immaturity in fetuses. The tically significant changes in mean percentages of fetuses with
increased embryo death rate at concentrations of 0.1, 0.3 and skeletal variations or any variations were observed compared to
4.0 mg/m3 Butyl Methacrylate was due to the pre-implantation concurrent controls. The investigators stated that the biological
death of embryos. relevance of these findings is limited because the observed
 ESTER MONOMERS USED IN NAIL ENHANCEMENT PRODUCTS 87

incidences occurred with no clear concentration-dependent incidental. The stomach had raised areas (2 animals), ulcerated
pattern. They considered these findings suggestive of slight areas (2 animals), and thickened and rough areas (1 animal)
fetotoxicity (Saillenfait et al. 1999). in the nonglandular mucosa and reddened ulcerated areas
(1 animal) and ulcerated areas (2 animals) in the glandular.
HEMA Pregnancy rates, mean number of corpora lutea and implan-
The Ministry of Health and Welfare: Japan (1998) reported tations, as well as mean implantation efficiency were compara-
the results of a study in which the reproductive/developmental ble between the control and Trimethylolpropane Trimethacry-
toxicity of HEMA was assessed in groups of 12 male and 12 late treated groups. Fetotoxic effects such as increased resorp-
female rats dosed with 0, 30, 100, 300, and 1000 mg/kg/day of tions (mean incidence 25.4%), decreased fetal viability (mean
HEMA by gavage. Males were dosed for 49 days and females survival 74.6%), decreased fetal weights, and decreased fetal
were dosed from 14 days before mating to day 3 of lactation. All lengths were observed in Trimethylolpropane Trimethacrylate
male rats were killed on day 50 and female rats were killed on day treated rats. Decreases in mean gravid uterine weights (control,
4 of lactation. The NOEL was 1000 mg/kg/day for reproductive 69.48; treated, 46.81) were also noted and attributed to feto-
and developmental effects. HEMA showed no effects on any toxic effects. The fetal effects were considered directly related
reproductive parameters of the parental males or developmental to the maternal toxicity of Trimethylolpropane Trimethacrylate
parameters of the offspring (Ministry of Health and Welfare: (Hazelton Laboratories 1983).
Japan 1998).
Dermal
Andrews and Clary (1986) evaluated the teratogenic poten-
Hydroxypropyl Methacrylate
tial of Trimethylolpropane Trimethacrylate using rats. A single
The Ministry of Health and Welfare: Japan (1998) reported dose of Trimethylolpropane Trimethacrylate was administered
the results of a study in which the reproductive/developmental dermally to 20 pregnant rats during days 6 to 15 of gestation.
toxicity of Hydroxypropyl Methacrylate was assessed in groups The authors stated that Trimethylolpropane Trimethacrylate
of 12 male and 12 female rats dosed with 0, 30, 100, 300, and was fetotoxic at a maternally toxic dose of 2500 mg/kg/day.
1000 mg/kg/day of Hydroxypropyl Methacrylate by gavage. Decreased fetal body weight and crown-rump distance was ob-
Males were dosed for 49 days and females were dosed from served. The data was inconclusive regarding teratogenic po-
14 days before mating to day 3 of lactation. All male rats were tential since the number of fetuses examined was very small
killed on day 50 and female rats were killed on day 4 of lactation. (Andrews and Clary 1986).
The NOAEL was 1000 mg/kg/day for reproductive and de-
velopmental effects. Hydroxypropyl Methacrylate showed no
effects on any reproductive parameters of the parental males or GENOTOXICITY
developmental parameters of the offspring (Ministry of Health Bacterial Test Systems
and Welfare: Japan 1998). Butyl Methacrylate
Butyl Methacrylate was not mutagenic in an Ames muta-
Trimethylolpropane Trimethacrylate genesis assay using Salmonella typhimurium strains TA1535,
Oral TA1537, TA1538, TA98 and TA100 with and without metabolic
Hazelton Laboratories (1983) evaluated the teratogenic ef- activation at concentrations of 60, 120, 180, 240 and
fects of Trimethylolpropane Trimethacrylate administered by 300 μg/plate. A solvent control of ethanol and three positive
gavage to pregnant rats on days 6 to 15 of gestation. Twenty- controls were also included (Haskell Laboratories 1977c).
two female rats received 2500 mg/kg/day of Trimethylolpropane Gould (1987) reported that Butyl Methacrylate was not mu-
Trimethacrylate; control rats received corn oil only. Maternal tagenic in an Ames Salmonella mutagenicity assay.
and fetal data were evaluated for treatment-related effects. The Mobil Oil Corporation (1990) reported a study in which
There were two deaths and body weight gains (for the Butyl Methacrylate was incubated with S. typhimurium strain
total gestation period) were decreased in Trimethylolpropane TA1538 in plates with metabolic activation at concentrations of
Trimethacrylate-treated rats. There was an increased incidence 10.0 μl/50 μl, 3.1 μl/50 μl, 0.97 μl/50 μl, 0.30 μl/50 μl, 0.094
of clinical signs from Trimethylolpropane Trimethacry- μl/50 μl, 0.029 μl/50 μl, 0.0092 μl/50 μl and 0.0028 μl/50
late exposure such as wheezing (3 animals), rough hair coat μl. A positive control of 2.0 μg 2-aminoanthracene was also
(5 animals), hunched posture (9 animals), soft feces (2 animals), used. Butyl Methacrylate was mutagenic (20-fold increase in
urine stains (13 animals), thin appearance (6 animals), dyspnea revertants/plate compared to controls) at all concentrations in
(5 animals), salivation (1 animal), alopecia (12 animals), bloody strain TA1538 with metabolic activation in this test system. The
crust (4 animals), and red vaginal discharge (3 animals). There response was concentration-related.
was an increased incidence of gross pathology findings (9 In a follow-up study, The Mobil Oil Corporation (1991)
of 22 animals); although the most common were in the liver incubated Butyl Methacrylate with S. typhimurium strains
(tan areas) and kidney (pelvis dilated), they were considered TA98, TA100, TA1535, TA1537 and TA1538 with and
88 COSMETIC INGREDIENT REVIEW

without metabolic activation at concentrations of 0.30 μl/50 μl, Hydroxylpropyl Methacrylate

0.094 μl/50 μl, 0.029 μl/50 μl, 0.0092 μl/50 μl and 0.0028 The Ministry of Health and Welfare: Japan (1998) reported
μl/50 μl. Four positive controls were included. Butyl Methacry- on the mutagenicity of Hydroxylpropyl Methacrylate in S. ty-
late was not mutagenic with or without metabolic activation in phimurium (strains TA98, TA100, TA1535, and TA1537) and E.
this test system. coli (WP2 uvrA). The dose range tested was from 313 to 5000
The Ministry of Health and Welfare: Japan (1998) reported μg/plate with and without metabolic activation. Hydroxypropyl
on the mutagenicity of Butyl Methacrylate using S. typhimurium Methacrylate was not mutagenic at any dose tested (Ministry of
(strains TA98, TA100, TA1535, and TA1537) and E. coli (WP2 Health and Welfare: Japan, 1998).
uvrA). The dose range tested was from 9.77 to 313 μg/plate
without metabolic activation and 9.77 to 1250 μg/plate with Trimethylolpropane Trimethacrylate
metabolic activation. Butyl Methacrylate was not mutagenic at In its workplace exposure guide, the American Industrial
any dose tested. Hygiene Association (1981) stated that Trimethylolpropane
Trimethacrylate was negative in the Ames test with and without
metabolic activation.
t-Butyl Methacrylate
The Ministry of Health and Welfare: Japan (1998) reported Multiple Methacrylate Esters
on the mutagenicity of t-Butyl Methacrylate in S. typhimurium Waegemaekers and Bensink (1984) reported that Butyl
(strains TA98, TA100, TA1535, and TA1537) and E. coli (WP2 Methacrylate, t-Butyl Methacrylate, HEMA, and Hexyl
uvrA). The dose range tested was from 9.77 to 625 μg/plate with- Methacrylate were not mutagenic in an Ames mutagenesis assay
out metabolic activation and 9.77 to 625 μg/plate with metabolic usingS. typhimurium strains TA1535, TA1537, TA1538, TA98
activation. t-Butyl Methacrylate was not mutagenic at any dose and TA100 with and without metabolic activation at concen-
tested. trations of 40, 160, 625 and 2500 μg/plate. Solvent controls,
positive controls and sterility controls for the S9 mix were per-
Ethylene Glycol Dimethacrylate formed with each experiment.
The mutagenicity of Ethylene Glycol Dimethacrylate was The US EPA (1985) reported on the mutagenicity of
tested in S. typhimurium strain TA100 with and without Butyl Methacrylate, t-Butyl Methacrylate, Ethylene Gly-
metabolic activation at concentrations from 0.01 to 1.0 μl/plate. col Dimethacrylate, HEMA, Hexyl Methacrylate, Isobutyl
Ethylene Glycol Dimethacrylate was mutagenic at 0.5 and Methacrylate, PEG-4 Dimethacrylate, and Trimethylolpropane
1.0 μl/plate with metabolic activation and at 0.5 μl/plate without Trimethacrylate in the Ames assay. The strains and doses used
metabolic activation (Rohm and Haas Co. 1980). were not stated. None of the chemicals listed above were muta-
genic in the Ames assay. No details were available.
Zeiger et al. (1987) tested Butyl Methacrylate and Isobutyl
HEMA Methacrylate in S. typhimurium strains TA98, TA100, TA1535,
The mutagenicity of HEMA was evaluated with and with- TA1537 and/or TA97 with and without metabolic activation at
out metabolic activation in S. typhimurium (strains TA98 and doses of 0, 1.0, 3.3, 10.0, 33.0, 100.0, 333.0, 1000.0, 3333.0
TA100) and E. coli (strains R P2, uvrA, and WP2). HEMA was or 10000.0 μg/plate. At least five doses of the chemical were
tested at concentrations from 0.2 to 1000 μg/ml. There was a tested in triplicate. Concurrent solvent and positive controls were
slight increase in revertants over the control level in TA100 but analyzed with each trial. Sodium azide, 9-aminoacridine and 4-
the increase was not consistent or dose-related. The researchers nitro-o-phenylene-diamine were used as positive controls in the
concluded that HEMA was not mutagenic in the assays tested absence of metabolic activation. The positive control used with
(British Petroleum Company 1981). metabolic activation was 2-aminoanthracene. Butyl Methacry-
Schweikl et al. (1994) tested HEMA in S. typhimurium strains late and Isobutyl Methacrylate were negative for mutagenicity
TA97a, TA98, TA100, TA102, and TA104 with and without in this test system.
metabolic activation at doses of 0, 0.005, 0.025, 0.05, 0.25, 0.50, Cameron et al. (1991) assessed the genotoxicity of Ethylene
1.25, 2.50, 3.75, 5.00, 12.5, and 25.0 mg/plate. The mean number Glycol Dimethacrylate and Trimethylol propane Trimethacry-
of revertants per plate were scored and experiments were done in late in the Salmonella/ mammalian microsome assay and
triplicate. HEMA was not mutagenic with or without metabolic the mouse lymphoma TK+/− assay. In the Salmonella/
activation in all strains tested. Controls gave the expected results. mammalian microsome assay, Ethylene Glycol Dimethacrylate
The Ministry of Health and Welfare: Japan (1998) reported was tested at 100, 333, 1000, 3333, and 10,000 μg/plate with
on the mutagenicity of HEMA in S. typhimurium (strains TA98, and without metabolic activation (S9) and Trimethylolpropane
TA100, TA1535, and TA1537) and E. coli (WP2 uvrA). The dose Trimethacrylate was tested at 333, 1000, 3333, 6667, and
range tested was from 313 to 5000 μg/plate without metabolic 10,000 μg/plate with and without metabolic activation. The
activation and 313 to 5000 μg/plate with metabolic activation. Salmonella typhimurium strains TA 98, TA100, TA 1535, and
HEMA was not mutagenic at any dose tested. TA 1537 were used. The solvent DMSO was the negative
 ESTER MONOMERS USED IN NAIL ENHANCEMENT PRODUCTS 89

control and the positive controls were 2-nitrofluorene (TA 98), Mammalian Test Systems
sodium azide (TA 100 and TA 1535), and 9-aminoacridine (TA Butyl and t-Butyl Methacrylate
1537) for the non-activation study and 2-aminoanthracene for The Ministry of Health and Welfare: Japan (1998) reported
the activation study. In the mouse lymphoma TK+/− assay, results of chromosomal aberration tests used to assess the ef-
Ethylene Glycol Dimethacrylate was tested at 4.76 × 10−4 to fect of Butyl Methacrylate and t-Butyl Methacrylate on Chinese
1.58 × 10−3 without activation and 4.76 × 10−4 to 6.88 × 10−3 hamster lung cells.
with activation (S9); Trimethylolpropane Trimethacrylate was Butyl Methacrylate was used at doses from 0 to 1420 μg/ml
tested at 6.57 × 10−5 to 1.63 × 10−4 without activation and with and without metabolic activation. Mitomycin C was the
2.19 × 10−4 to 5.32 × 10−4 with metabolic activation. positive control for the non-activation study and cyclophos-
Ethylene Glycol Dimethacrylate was negative with and with- phamide was the positive control for the activation study. Butyl
out metabolic activation. Trimethylol propane Trimethacry- Methacrylate did not induce structural chromosomal aberrations
late was negative in the Salmonella/mammalian microsome at the doses tested.
assay without metabolic activation, but was weakly posi- t-Butyl Methacrylate was used at doses from 0 to 400 μg/ml,
tive with S9 metabolic activation. In the mouse lymphoma 0 to 200 μg/ml, and 0 to 700 μg/ml without metabolic activa-
TK+/− assay, Ethylene Glycol Dimethacrylate was nega- tion for a 24 hour treatment, 48 hour treatment, and a 6 h pulse
tive without metabolic activation but was positive with S9 treatment, respectively. t-Butyl Methacrylate was tested at doses
metabolic activation. Trimethylol propane Trimethacrylate was from 0 to 750 μg/ml for a 6 hour pulse treatment with metabolic
negative in the mouse lymphoma TK+/− assay with and with- activation. Mitomycin C was the positive control for the non-
out metabolic activation at all doses tested (Cameron et al. activation study and benzo[a]pyrene was the positive control
1991). for the activation study. t-Butyl Methacrylate only induced clas-
Heil et al. (1996) tested the mutagenicity of HEMA, togenicity at 400 μg/ml in the 24-hour treatment (Ministry of
Isopropylidenediphenyl Bisglycidyl Methacrylate, Triethylene Health and Welfare: Japan 1998).
Glycol Dimethacrylate, and Di-HEMA Trimethylhexyl Di-
carbamate in S. typhimurium strains TA97a, TA98, TA100,
Ethylene Glycol Dimethacrylate
and TA102 with and without metabolic activation at doses
of 0, 0.25, 0.50, 1.25, 5.00 and 12.5 mg/plate. The mean Litton Bionetics (1985) tested Ethylene Glycol Dimethacry-
number of revertants per plate were scored and experiments late in the L5178Y mouse lymphoma cell assay. The induction
were done in triplicate. HEMA, Isopropylidenediphenyl Bisg- of forward mutations was examined. L5178Y/TK+/− cells were
lycidyl Methacrylate, Triethylene Glycol Dimethacrylate, and treated with 3.9 to 800 nl/ml of Ethylene Glycol Dimethacrylate
Di-HEMA Trimethylhexyl Dicarbamate were not mutagenic in with and without exogenous activation. Negative control cells
the Ames assay with or without metabolic activation in all strains were treated with DMSO and positive control cells were treated
tested. Controls gave the expected results. with ethylmethane sulfonate for the nonactivation studies and
These authors also screened HEMA, Isopropylidenediphenyl dimethylnitrosamine for the activation studies.
Bisglycidyl Methacrylate, and Di-HEMA Trimethylhexyl Di- Ethylene Glycol Dimethacrylate significantly induced dose-
carbamate for mutagenicity using three tests: the bacterial umu- related increases in the mutation frequency in L5178Y mouse
test in Salmonella typhimurium strain TA1535/pSK1002, the lymphoma cells with metabolic activation at concentrations from
eukaryotic DNA synthesis inhibition test (DIT), and the in vivo 400 to 700 nl/ml. Without metabolic activation, concentrations
alkaline filter elution (AFE) technique. HEMA was tested at 0.2 up to 800 nl/ml caused high toxicity without increasing mu-
to 20 mM in the umu-test, 0.3 to 40 mM in the DIT, and at tation frequency. Ethylene Glycol Dimethacrylate was consid-
2 mM in the AFE technique. Isopropylidenediphenyl Bisgly- ered active in the mouse lymphoma forward mutation assay with
cidyl Methacrylate was tested at 1.3 to 150 mM in the umu-test, metabolic activation (Litton Bionetics 1985).
0.02 to 0.6 mM in the DIT, and at 2 mM in the AFE technique.
Di-HEMA Trimethylhexyl Dicarbamate was tested at 0.2 to 6 HEMA
mM in the umu-test, 0.1 to 6 mM in the DIT and at 2 mM in the The Ministry of Health and Welfare: Japan (1998) reported
AFE technique. on a chromosomal aberration test used to assess the effect of
HEMA was negative at all concentrations tested in the HEMA on Chinese hamster lung cells. HEMA was tested using
umu-test, DIT, and AFE technique. Isopropylidenediphenyl 24-hour continuous treatment, 48-hour continuous treatment,
Bisglycidyl Methacrylate was negative at all concentrations and a short-term treatment. HEMA was tested with and without
tested in the umu-test and AFE technique; however, Isopropy- metabolic activation.
lidenediphenyl Bisglycidyl Methacrylate was positive in the Chromosomal aberrations were induced at 0.65 and
DIT at concentrations at or greater than 0.08 mM. Di-HEMA 1.3 mg/ml (mid and high concentration) with 24-hour contin-
Trimethylhexyl Dicarbamate was negative at all concentrations uous treatment, at 0.16 to 0.65 mg/ml (all concentrations) with
tested in the umu-test, and DIT; it was limited positive using the 48-hour continuous treatment and at 1.3 mg/ml (high concentra-
AFE technique (Heil et al. 1996). tion) with short-term treatment and metabolic activation. HEMA
90 COSMETIC INGREDIENT REVIEW

induced polyploidy at 0.65 mg/ml with 48-hour continuous treat- Trimethylolpropane Trimethacrylate did not increase mu-
ment and at 0.33 and 1.3 mg/ml (low and high concentrations) tation frequencies in treated cells as compared to control
with short-term treatment without metabolic activation (Min- cells without metabolic activation even at the relatively toxic
istry of Health and Welfare: Japan 1998). dose of 80 nl/ml. However, with activation Trimethylolpropane
Trimethacrylate induced an increase in mutations at the TK lo-
Hydroxypropyl Methacrylate
cus in L5178Y mouse lymphoma cells at doses of 100 to 200
The Ministry of Health and Welfare: Japan (1998) reported nl/ml (moderately to highly toxic) with microsomal activation
on a chromosomal aberration test used to assess the effect of Hy- (Litton Bionetics 1979).
droxypropyl Methacrylate on Chinese hamster lung cells. Hy- In a workplace exposure guide, the American Industrial
droxypropyl Methacrylate was used at doses from 0 to 1.4 mg/ml Hygiene Association (1981) stated that Trimethylolpropane
with and without metabolic activation in a short-term treatment Trimethacrylate was positive in the mouse lymphoma forward
and at 0 to 0.70 mg/ml without metabolic activation in a con- mutation assay with and without metabolic activation. No other
tinuous treatment. Mitomycin C was the positive control for the details were available.
non-activation study and cyclophosphamide was the positive Schweikl and Schmalz (1999) studied the effect Triethylene
control for the activation study. Glycol Dimethacrylate had on V79 cell cultures. Triethylene
Hydroxypropyl Methacrylate without metabolic activation Glycol Dimethacrylate was tested at concentrations from 0 to
(continuous treatment) induced clastogenicity at 0.35 mg/ml and 1.00 mmol/l. Triethylene Glycol Dimethacrylate caused a dose-
polyploidy at 0.18 mg/ml. Hydroxypropyl Methacrylate without dependent increase in the number of micronuclei in V79 cells.
metabolic activation (short-term treatment) induced clastogenic- Triethylene Glycol Dimethacrylate treated V79 cell cultures had
ity at 1.4 mg/ml. Hydroxypropyl Methacrylate with metabolic only one cell clone among a total of 25 that contained all exon
activation (short-term treatment) induced clastogenicity at 0.35 sequences of the hprt gene. Large DNA sequences were deleted
mg/ml and polyploidy at 0.35 mg/ml (Ministry of Health and in 24 cell clones. The researchers concluded that the induction of
Welfare: Japan 1998). large DNA sequence deletions is probably common for acrylate
Isopropylidenediphenyl Bisglycidyl Methacrylate and methacrylates.
Litton Bionetics (1985) tested Isopropylidene-diphenyl Bis-
glycidyl Methacrylate in the L5178Y mouse lymphoma cell Multiple Methacrylate Esters
assay. The induction of forward mutations was examined. Dearfield et al. (1989) tested PEG-4 Dimethacrylate and
L5178Y/TK+/− cells were treated with Isopropylidenediphenyl Trimethylolpropane Trimethacrylate in the L5178Y mouse lym-
Bisglycidyl Methacrylate at 0.586 nl/ml to 160 nl/ml (without phoma cell assay. The induction of mutations, aberrations and
metabolic activation) and up to 350 nl/ml (with metabolic ac- micronuclei was examined. L5178Y/TK+/− cells were treated
tivation). Negative control cells were treated with DMSO and with 75–525 μg/ml of PEG-4 Dimethacrylate without exoge-
positive control cells were treated with ethylmethane sulfonate nous activation for 4 h or 5–50 μg/ml of Trimethylolpropane
for the nonactivation studies and dimethylnitrosamine for the Trimethacrylate without exogenous activation for 4 h. Control
activation studies. cells were treated with the solvent (dimethylsulfoxide) alone.
Isopropylidenediphenyl Bisglycidyl Methacrylate induced Cytogenic analyses were conducted on 200 cells per treatment
small increases in the mutation frequency in L5178Y mouse group following cell treatment and washing. Other cells were
lymphoma cells with metabolic activation at concentrations maintained in log-phase growth for two days and then cloned
from 200 to 350 nl/ml. Without metabolic activation, concen- with and without trifluorothymidine (TFT) selection. Following
trations up to 140 nl/ml caused high toxicity without inducing an incubation period of 9–11 days, the colonies were counted
increased mutantion frequency. Isopropylidenediphenyl Bisg- and sized.
lycidyl Methacrylate was considered weakly mutagenic in the PEG-4 Dimethacrylate increased the mutation frequency to
mouse lymphoma forward mutation assay with metabolic acti- 491 × 10−6 and the maximum response was at 525 μg/ml which
vation (Litton Bionetics 1985). allowed 14% survival. PEG-4 Dimethacrylate induced signifi-
cant levels of aberrations (70 per 100 cells). Trimethylolpropane
Triethylene Glycol Dimethacrylate Trimethacrylate was also found to increase the mutation fre-
Litton Bionetics (1979) tested Trimethylolpropane Trimet- quency in mouse lymphoma cells, however the activity was con-
hacrylate in the L5178Y mouse lymphoma cell assay. sidered weak. The mutation frequency was increased to 163 ×
L5178Y/TK+/− cells were treated with Trimethylolpropane 10−6 and the maximum response was at 50 μg/ml which allowed
Trimethacrylate at 0.156 nl/ml to 80 nl/ml (without metabolic 11% survival. Trimethylolpropane Trimethacrylate produced
activation) and up to 400 nl/ml (with metabolic activation). aberrations (20 per 100 cells) but did not induce micronuclei.
Negative control cells were treated with DMSO and positive Primarily, small-colony TFT-resistant mutants were induced
control cells were treated with ethylmethane sulfonate for the which the researchers suggested that genotoxicity was likely
nonactivation studies and dimethylnitrosamine for the activation due to a clastogenic mechanism. This was supported further by
studies. increased aberration and micronucleus frequencies in PEG-4
 ESTER MONOMERS USED IN NAIL ENHANCEMENT PRODUCTS 91

Dimethacrylate, but Trimethylolpropane Trimethacrylate did size and complexity of Butyl, Isobutyl, and Lauryl Methacry-
not have an increased micronucleus frequency (Dearfield et al. late as well as other methacrylate monomers that may be found
1989). in nail preparations, militates against their being genotoxic, in
Schweikl et al. (1998) tested the mutagenicity of HEMA, the absence of actual test data.” This conclusion was based upon
Isopropylidenediphenyl Bisglycidyl Methacrylate, Triethylene negative results in several bacterial tests and weakly positive
Glycol Dimethacrylate, and Di-HEMA Trimethylhexyl Dicar- mammalian tests (most likely due to a clastogenic mechanism)
bamate in V79 cells with and without metabolic activation. The on ethyl methacrylate and methyl methacrylate.
chemicals were tested at the following concentrations HEMA
(0, 2.5, and 5.0%) Isopropylidenediphenyl Bisglycidyl
Methacrylate (0, 25, and 50%), Triethylene Glycol Dimethacry- CARCINOGENICITY
late (0, 0.5, and 1%), and Di-HEMA Trimethylhexyl Dicarba- PEG-4 Dimethacrylate
mate (0, 25, 50, and 75%). The positive control was 200 μg/ml Andrews and Clary (1986) reported on the chronic dermal
ethylmethane sulfonate. exposure of PEG-4 Dimethacrylate using mice. Mice were given
HEMA, Isopropylidenediphenyl Bisglycidyl Methacrylate, 25 mg of PEG-4 Dimethacrylate, twice weekly for 80 weeks.
and Di-HEMA Trimethylhexyl Dicarbamate were clearly not No remarkable skin irritation was noted although acanthosis and
mutagenic with or without metabolic activation. Triethylene fibrosis were evident. No increased incidence of skin or visceral
Glycol Dimethacrylate had a dose-dependent increase in mutan- tumors were observed. Six of 50 mice died during the study. No
tion frequency in V79 cell cultures without metabolic activation. other details were available (Andrews and Clary 1986).
However, the mutagenicity of Triethylene Glycol Dimethacry-
late was destroyed in the presence of metabolic activation. The
researchers concluded that Triethylene Glycol Dimethacrylate Triethylene Glycol Dimethacrylate
acted through a clastogenic mechanism which is not detected by The Bushy Run Research Center (1995) evaluated the car-
Ames tester strains (Schweikl et al. 1998). cinogenicity of Triethylene Glycol Dimethacrylate in a skin
painting study using C3H/HeNHsd male mice. Each test group
Ethyl Methacrylate had 70 male mice. The three treatment groups received concen-
Moore et al. (1988) tested Ethyl Methacrylate in the L5178Y trations of 5, 25, or 50% Triethylene Glycol Dimethacrylate (in
mouse lymphoma cell assay. L5178Y/TK+/− cells were treated acetone) applied to the dorsal skin of mice at a dose volume
with 900–2100 μg/ml of Ethyl Methacrylate without exogenous of 50 μl for 5 days/week for 78 weeks. The two control groups
activation for 4 h. Control cells were treated with the solvent were the untreated control and the vehicle control (acetone only).
(dimethylsulfoxide) alone. Cytogenic analyses were conducted Epidermal cell proliferation was evaluated after 4, 13, 52, and
on 200 cells per treatment group following cell treatment and 78 weeks of the study. Animals were monitored for toxicity (clin-
washing. Other cells were maintained in log-phase growth for ical signs and palpable masses), body weight, body weight gain,
two days and then cloned with and without TFT selection. Fol- hematology, clinical chemistry, organ weights, gross pathology,
lowing an incubation period of 9-11 days, the colonies were and histopathology.
counted and sized. Triethylene Glycol Dimethacrylate did not result in any
Cytotoxicity was only observed at concentrations greater treatment-related changes in hematology, clinical chemistry,
than 1000 μg/ml. Toxicity plateaued at concentrations above mean absolute body weight or body weight gain when applied
1500 μg/ml, where survival fluctuated from 2–37%. A weak cutaneously. There was decreased survival in the mid-dose and
positive response was observed in cultures with 10–20% sur- high-dose groups, but only the high-dose group was significantly
vival (1,450, 1,500, 1,550, and 1,626 μg/ml). The greatest num- different from the controls. Clinical signs of irritation (primarily
ber of aberrations occurred at a concentration of 1626 μg/ml exfoliation) were observed in all dose groups and their onset
(16% survival) where there were 83 mutants/106 survivors and and severity were dose dependent. High-dose mice that died
11 aberrations/200 cells. or were sacrificed moribund had an increased incidence of
Some of the cultures with less than 10% survival had mutation hepatocellular adenomas and carcinomas, the overall incidence
frequencies three times greater than background. The colony of these tumors was similar across all dose groups. There were
size distribution was difficult to determine; however, the re- no other microscopic lesions in the mid- or high-dose groups
searchers did note that cultures with mutation frequencies of that were considered to be responsible for increased mortality,
200 mutants/106 survivors (less than 10% survival) had an in- however a statistically significant increased kidney size was
duction of primarily small colonies. The researchers suggested observed in these groups. The researchers could not definitively
that the genotoxicity of Ethyl Methacrylate was likely due to a identify the cause for increased mortality in mid- and high-dose
clastogenic mechanism (Moore et al. 1988). groups; they felt that the cutaneous irritation was not severe
Jackson (2001) reported a structure activity relationship anal- enough to result in the increased mortality, but instead the
ysis of the genotoxic potential of Butyl, Isobutyl, and Lauryl increased kidney weights may have been related to the increased
Methacrylate. Jackson determined that due to “the increasing mortality. The NOEL for Triethylene Glycol Dimethacrylate
92 COSMETIC INGREDIENT REVIEW

was 5%. The researchers concluded that Triethylene Glycol Dermal Sensitization
Dimethacrylate did not induce carcinogenicity at any dose level FDA (1976) reported that the contact sensitization potentials
tested (Bushy Run Research Center 1995). of 1% Butyl Methacrylate, 1% Hydroxypropyl Methacrylate,
and 1% Isobutyl Methacrylate in petrolatum were determined
Trimethylolpropane Trimethacrylate in 12 volunteers. A standard Draize test was used in which the
Andrews and Clary (1986) reported that the chronic dermal Methacrylate test monomer was applied 10 times to the same
exposure of Trimethylolpropane Trimethacrylate was evaluated site three times weekly, every 48 h during the week and 72 h on
using mice. Mice were given 25 mg of Trimethylolpropane the weekend. The site was occluded and a nontreatment period
Trimethacrylate twice weekly for 80 weeks. No remarkable skin followed by a 72 h final elicitation at a new site.
irritation was noted although acanthosis and fibrosis were evi- One of 12, 0 of 11, 0 of 12, and 0 of 11 patients reacted posi-
dent. No increased incidence of skin or visceral tumors were tively to Butyl Methacrylate, HEMA, Hydroxypropyl Methacry-
observed. Five of 50 mice died during the study. No other de- late, and Isobutyl Methacrylate, respectively (FDA 1976).
tails were available. In its workplace exposure guide, the American Industrial
Hygiene Association (1981) stated that Trimethylolpropane
Methyl Methacrylate Trimethacrylate has been shown to be a human sensitizer in
An update to its Methyl Methacrylate monograph was pub- patch tests. No details were available.
lished by the International Agency for Research on Cancer In a review article, Geurtsen (2000) stated that Ethylene
(IARC) in 1994 (IARC 1994). Methyl Methacrylate had no Glycol Dimethacrylate, HEMA, Isopropylidenediphenyl Bisg-
adverse reproductive effects by inhalation exposure in rats lycidyl Methacrylate, Triethylene Glycol Dimethacrylate, and
and mice and there were no data available on the genetic Di-HEMA Trimethylhexyl Dicarbamate were considered to be
and related effects of methyl methacrylate in humans. Methyl capable of causing hypersensitivity/allergy in humans. No de-
methacrylate caused chromosomal aberrations in rat bone mar- tails were available.
row but did not induce micronuclei in mouse bone marrow
in vivo. Gene mutation, sister chromatid exchange, micronu- Reproductive and Developmental Toxicity
clei and chromosomal aberrations were induced in mammalian Jelovsek et al. (1989), predicated on an Isobutyl Methacry-
cells in vitro. The IARC working group concluded that there late developmental toxicity study in rats that produced positive
is inadequate evidence in humans for the carcinogenicity of results, used logistic regression and discriminant analysis to pre-
methyl methacrylate and there is evidence suggesting a lack dict its effect in humans. The authors concluded that Isobutyl
of carcinogenicity in experimental animals. Methyl Methacry- Methacrylate was not considered a developmental toxicant in
late is not classifiable as to its carcinogenicity to humans humans.
(Group 3).
Lomax et al. (1997) exposed male and female Fischer 344 Case Reports
rats (70 males and 70 females/group) to Methyl Methacry- A 50-year-old woman used artificial nails for 1.5 years and
late monomer vapors at 0, 25, 100, and 400 ppm (6 h/day, for several months prior to seeking treatment, a paronychial and
5 days/week) for 24 months and female Golden hamsters (53– eyelid dermatitis occurred two days after each new application
55 males and 56–59 females/group) were exposed to similar of artificial nails. Patch test results using 5% Butyl Methacry-
concentrations for 18 months. Animals were monitored for clin- late in petrolatum and 1% Butyl Methacrylate in ethyl alcohol
ical signs, body weights, hematology, clinical chemistry (rats demonstrated +2 reactions (erythema, papules, and vesicles) at
only), and urinalyses (rats only). Ten rats per sex/per group were 48 and 96 hours. Methyl methacrylate and ethyl methacrylate at
killed after week 13 and 52, all surviving rats were killed during 5% in petrolatum or 1% in ethyl alcohol caused +2 reactions at
weeks 104 to 106. All surviving hamsters were killed at week 48 and 96 hours. The eyelid and paronychial dermatitis resolved
78. with discontinuation of artificial nail usage (Marks et al. 1979).
Chronic exposure to methyl methacrylate vapor did not cause A 28-year-old black male had dermatitis of his hands, nausea
tumors in hamsters or rats (Lomax et al. 1997). and diarrhea associated with exposure to an 80% HEMA solution
and subsequent positive patch tests to HEMA. Cross reactivity
CLINICAL ASSESSMENT OF SAFETY patch tests that contained 5% Butyl Methacrylate or 5% Isobutyl
Methacrylate in petrolatum were negative (Mathias et al. 1979).
Dermal Irritation Two patients patch tested with 1% Butyl Methacrylate or 1%
In a workplace exposure guide, the American Industrial Isobutyl Methacrylate monomer in petrolatum had markedly
Hygiene Association (1981) stated that Trimethylolpropane positive reactions. They also had positive reactions to other
Trimethacrylate was a mild to moderate skin irritant in a sin- acrylic monomers, with the exception of methacrylic acid
gle application patch test (number of volunteers not given) (Fisher 1980).
at concentrations of 1% and 10%. At 0.1% there was no A 17-year-old female working in the manufacture and appli-
irritation. cation of artificial nails had exudative, itchy lesions on or around
 ESTER MONOMERS USED IN NAIL ENHANCEMENT PRODUCTS 93

the nails of her fingers. She had a previous history of metal al- glue and all were negative except an elderly woman who had
lergy. She was patch tested with a standard series of plastics and a weak irritant reaction. The researchers could not rule out the
acrylates. She had a +1 reaction at 48 hours and a +2 reaction at possibility that the hairdresser’s reactions may be due to the
96 hours to 2% HEMA in petrolatum. She also reacted positively contaminants in the ethyl cyanoacrylate nail glue (Jacobs and
to methyl and ethyl methacrylate (Condé-Salazar et al. 1986). Rycroft 1995).
A case of occupational allergic contact dermatitis was re- A 38-year-old non-atopic woman had developed allergic con-
ported in a 20-year-old dental assistant. After 3 months of work- tact dermatitis from textile dyes but had been without symp-
ing with dental resins, she developed a hand eczema on the fin- toms. She had been working installing car rear-view mirrors on
gers of the right hand which spread to the left hand and eyelids. a production line for the past 6 years. For 2 years she had been
She had been handling materials without gloves. She was given experiencing a dry and fissured dermatitis on both hands. The
the dental screening series patch test. She had a +2 reaction to dermatitis spread to her arms, chest, neck, and face and she de-
Isopropylidenediphenyl Bisglycidyl Methacrylate (2%) and had veloped rhinitis and tenderness of the mucous membranes of the
a positive reaction to concentrations as low as 0.0002%. Twenty nose. She also had paresthesia of the fingertips but her dermati-
control people were tested and none had a positive reaction tis cleared while she was away from work. She was patch tested
(Kanerva et al. 1986). with the expoxy and methacrylate series. Penloc glue was used
Seven patients (6 dental nurses and a dentist) had been occu- to adhere the rear-view mirror to the windshield, it was found
pationally sensitized to dental resin products. Five patients were to contain by GC-MS, Ethylene Glycol Dimethacrylate (0.4%),
patch tested using Ethylene Glycol Dimethacrylate, HEMA, HEMA (24.6%), and Tetrahydrofurfuryl Methacrylate (% not
Hydroxypropyl Methacrylate, Isopropylidene-diphenyl Bisgly- stated). The major component was isobornyl acrylate (61.9%).
cidyl Methacrylate, Triethylene Glycol Dimethacrylate, and Di- The patient had +3 reactions to the Penloc glue at concentrations
HEMA Trimethylhexyl Dicarbamate. All materials tested were of 0.2, 0.6, and 2%. The patient was patch tested using Ethylene
at 2% concentration in petrolatum. Two patients reacted to Ethy- Glycol Dimethacrylate, HEMA, Hydroxypropyl Methacrylate,
lene Glycol Dimethacrylate with reactions ranging from +2 to Isopropylidenediphenyl Bisglycidyl Methacrylate, Tetrahydro-
+3. Three patients reacted to HEMA with reaction ranging from furfuryl Methacrylate, Triethylene Glycol Dimethacrylate, and
+1 to +3. Three patients reacted to Hydroxypropyl Methacry- Di-HEMA Trimethylhexyl Dicarbamate at a concentration of
late with reactions ranging from +2 to +3. Four patients re- 2%. The patient had no reaction to Isopropylidenediphenyl Bis-
acted to Isopropylidenediphenyl Bisglycidyl Methacrylate with glycidyl Methacrylate and Di-HEMA Trimethylhexyl Dicarba-
reactions varying from +2 to +4. Three patients reacted to Tri- mate. However, all other Methacrylates mentioned above re-
ethylene Glycol Dimethacrylate with reactions ranging from +2 sulted in +2 to +3 reactions (Kanerva et al. 1995).
to +4. Lastly, no patients reacted to Di-HEMA Trimethylhexyl A 47-year-old female cosmetician who had severe atopic der-
Dicarbamate (Kanerva et al. 1989). matitis in her youth, but had been without symptoms for 20
Freeman et al. (1995) reported 4 case reports involving years, developed dermatitis on her right thumb that subsequently
contact allergies to acrylates in acrylic nails. Four women, spread to both hands and face after she started to work with pho-
31 to 53 years old had adverse contact reactions from arti- tobonded nails and chemically cured nail cosmetics. Two patch
ficial nails. The clinical details included: fingertip dermatitis testing sessions were performed on the back (48-hour occlusion)
in 3 patients, nail fold dermatitis in 3 patients, nail dystrophy, using 2% Butyl Methacrylate, 2% Ethylene Glycol Dimethacry-
paresthesia, ulnar border hand dermatitis, and eyelid and neck late, 2% HEMA, 2% Hydroxypropyl Methacrylate, 2% Tetrahy-
dermatitis each present in one patient. All four patients were drofurfuryl Methacrylate, 2% Triethylene Glycol Dimethacry-
patch tested using 2% Ethylene Glycol Dimethacrylate, 2% Iso- late, and 2% Di-HEMA Trimethylhexyl Dicarbamate. Readings
propylidenediphenyl Bisglycidyl Methacrylate, and 2% PEG-4 were performed on days two, three and four. HEMA, Hydrox-
Dimethacrylate. Two of the patients had strong positive reac- ypropyl Methacrylate, Ethylene Glycol Dimethacrylate, and Tri-
tions to Ethylene Glycol Dimethacrylate and a third had a mild ethylene Glycol Dimethacrylate all resulted in a +2 reading in
positive reaction. None of the patients had reactions to the other this series of patch testing. There was a +1 reaction to Butyl
two Methacrylates. Methacrylate and no reactions to Tetrahydrofurfuryl Methacry-
A 24-year-old hairdresser and manicurist had nearly con- late and Di-HEMA Trimethylhexyl Dicarbamate. Additionally,
stant hand eczema for 6 years. She had been using various acry- the patient had an allergic patch test result to her own nail
lated nail glues over this time period. Her current nail glue was strengthener preparation that contained 2.2% Butyl Methacry-
99.95% ethyl cyanoacrylate and 0.005% undefined acrylic con- late and her own monomer liquid for sculptured nails with 5%
taminants. She was patch tested with the acrylates series and Triethylene Glycol Dimethacrylate (Kanerva et al. 1996).
her nail glue (10% in petrolatum). She reacted to Ethylene Gly- Case reports of female repair technicians of facsimile
col Dimethacrylate, HEMA, Hydroxypropyl Methacrylate, and machines, in which Butyl Methacrylate fumes were either not
her nail glue (as well as nickel, para-phenylenediamine, glyc- confirmed or confirmed up to 0.60 mg/m3 , reported symptoms
eryl thioglycolate, ethyl acrylate, methyl methacrylate, and ethyl of eye and upper respiratory tract irritation, chest tightness,
methacrylate). Fifteen controls were also tested with the nail congestion, dry cough, dyspnea, lung crackles and elevated
94 COSMETIC INGREDIENT REVIEW

immunoglobulin levels. All three cases improved upon removal and/or eyelid involvement, either alone or in combination with
of the repair technician from duties associated with facsimile nail finger changes. Typically, fingertip and/or periungual der-
machines. The authors stated that these descriptions suggest a matitis, with or without onycholysis developed in these pa-
link between Butyl Methacrylate and these abnormal clinical tients. In severe cases, painful paraesthesiae and Raynaud’s phe-
findings (Raymond 1996). nomenon may develop.
A 30-year-old male dentist had been using HEMA as a dentin A 49-year-old dental assistant had a long history of recur-
primer for 3 years. One day, he had an allergic reaction which rent eczema on her hands, forearms, upper eyelids and perio-
included redness, pruritus, sclerosis, and edema on his finger- ral area. She had erythematous, scaly, and fissured skin on her
tips whenever he handled a HEMA solution. A patch test was hands and forearms. Her face was red and scaly, and she had
conducted using HEMA at 35% and 100%. One volunteer with swollen eyelids. Symptoms would disappear when she was ab-
no history of sensitivity to dentin primers was used as a nega- sent from work. She was patch tested with 2% Ethylene Glycol
tive control. HEMA caused serious erythemic papules at both Dimethacrylate and had a +1 reaction at 2 days and a +2 re-
35% and 100% in the dentist. There was no reaction to water or action at 3 days. The researchers suspected she had airborne
vaseline (Katusuno et al. 1996). contact dermatitis since there was symmetrical involvement of
the upper eyelids and perioral area. This was confirmed when
Patch Testing Results her symptoms improved after avoiding acrylic resin exposure
Kanerva et al. (1988) patch tested 22 patients using 1% (Tosti et al. 1991).
Hydroxypropyl Methacrylate. Out of 22 patients exposed Three patients (two dental laboratory workers and one hear-
to acrylates, 3 patients tested positive to Hydroxypropyl ing aid laboratory worker) had allergic contact dermatitis from
Methacrylate. methacrylates. Symptoms disappeared when they avoided un-
Kanerva et al. (1988) used a commercial meth(acrylate) series cured methacrylates (light and chemically curable) in the work-
containing 28 Methacrylate and Acrylates on 24 patients. Ethy- place. Two of the patients also had conjunctivitis. These two
lene Glycol Dimethacrylate, HEMA, Hydroxypropyl Methacry- patients (dental assistant; hearing aid worker) were patch tested
late, Isopropylidenediphenyl Bisglycidyl Methacrylate, Triethy- and had positive reactions to Ethylene Glycol Dimethacrylate
lene Glycol Dimethacrylate, and Di-HEMA Trimethylhexyl (+3; +2), HEMA (+3; +2), Hydroxypropyl Methacrylate (+3;
Dicarbamate were part of the test series. All Methacrylates +2), and Triethylene Glycol Dimethacrylate (+3; +1). The re-
mentioned above were tested at a concentration of 2% (in searchers concluded that conjunctivitis may be caused by type IV
petrolatum). Out of 24 patients exposed to acrylates, only allergy, although type I allergy (even though prick tests were neg-
2 patients tested positive to Methacrylates. A dentist tested ative), other hypersensitivity mechanisms, or irritation cannot be
positive to Ethylene Glycol Dimethacrylate, HEMA, Hydrox- excluded (Estlander et al. 1996).
ypropyl Methacrylate, and Triethylene Glycol Dimethacry- Five women with photobonded acrylic nails had pruritic and
late. The second patient was a dental assistant that tested paronychial and subonychial dermatitis for several months and
positive to HEMA, Hydroxypropyl Methacrylate, Isopropyli- 2 patients had dermatitis of the lower lids and cheeks. The symp-
denediphenyl Bisglycidyl Methacrylate, and Triethylene Glycol toms developed 6 months to 3 years after the first applications of
Dimethacrylate. artificial nails. Monthly renewal of the nails caused a strong ex-
Tosti et al. (1993) patch tested 11 patients with occupational acerbation of the dermatitis within 24 hours. Patients were patch
allergic contact dermatitis from acrylate compounds. Five pa- tested with Ethylene Glycol Dimethacrylate (2.0%), HEMA
tients had a positive reaction to Ethylene Glycol Dimethacrylate, (0.02%, 0.2, and 0.6%), Hydroxypropyl Methacrylate (0.02,
one patient had a reaction to Triethylene Glycol Dimethacry- 0.2, and 0.6%), Isopropylidenediphenyl Bisglycidyl Methacry-
late, one patient had a reaction to Ethylene Glycol Dimethacry- late (2.0%), Triethylene Glycol Dimethacrylate (2.0%), and Di-
late, and another had a reaction to Ethoxyethyl Methacrylate. HEMA Trimethylhexyl Dicarbamate (0.2 and 0.6%). Five of five
Tucker and Beck (1999) reported that, over a 15-year pe- patients reacted positively to Ethylene Glycol Dimethacrylate
riod, 440 patients with a history of exposure to acrylates and (+2 and +3 reactions). Two patients (+1 reactions), 4 patients
methacrylates were patch tested with the Chemotechnique se-
R
(+2 reactions), and 5 patients (+3 reactions) reacted to 0.02%,
ries. Patch testing was done on the back and scored after 2 0.2%, and 0.6% HEMA, respectively. One patient (+2 reac-
days of occlusion and again on day 4. Patients patch tested with tion), 5 patients (+1 and +2 reactions), and 5 patients (+1, +2,
2% Ethylene Glycol Dimethacrylate (28/345 patients), 2% Iso- and +3 reactions) reacted positively to 0.02%, 0.2%, and 0.6%
propylidenediphenyl Bisglycidyl Methacrylate (5/281 patients), Hydroxypropyl Methacrylate, respectively. All patients had no
2% HEMA (29/337 patients), 2% Hydroxypropyl Methacry- reaction to Isopropylidene-diphenyl Bisglycidyl Methacrylate.
late (26/330 patients), 2% Triethylene Glycol Dimethacrylate Five of 5 patients reacted positively (1 patient was questionably
(21/343 patients), 2% Tetrahydrofurfuryl Methacrylate (5/147), positive) to Triethylene Glycol Dimethacrylate. One patient and
and 2% Di-HEMA Trimethylhexyl Dicarbamate (2/268 pa- two patients reacted positively to 0.2% (+1 reaction) and 0.6%
tients) elicited a positive response. Sixteen of the patients were (+1 and +2 reactions) Di-HEMA Trimethylhexyl Dicarbamate
sensitized via artificial nails; half of those patients had facial (Hemmer et al. 1996).
 ESTER MONOMERS USED IN NAIL ENHANCEMENT PRODUCTS 95

Consumer Adverse Reaction Reports Methacrylate; Triethylene Glycol Dimethacrylate; Trimethylol-

Consumers reported a number of injuries as a result of expo- propane Trimethacrylate, and Urethane Methacrylate are within
sure to nail adhesive for use with artificial nails. From 1995 to the same range as ethyl methacrylate since most are used in a
1997, reported individual reactions were dermatitis of the eye in system where ethyl methacrylate is the primary monomer. Ethyl
one person and dermatitis of the leg and hand in another person. methacrylate represents over 90% of the monomer used in nail
From 1987 to 1993, reported individual reactions were dermati- enhancing products. Thermal study data showed polymerization
tis of the face and lower trunk (to include the hips and external of 50% of the ethyl methacrylate monomer within 5 minutes.
genital area) in one patient, pain of the face in another patient, None of the Methacrylate monomers tested were shown to
and other injury complaints were noted to various parts of the have any endocrine disrupting activity.
body. It can be assumed that these injuries occurred as a result The reported oral LD50 values of Methacrylates were
of exposure to methacrylates in a system with ethyl methacry- >6.3 g/kg in rabbits, >2000 mg/kg to 25,530 mg/kg in rats,
late as the primary monomer since there are a limited number and 16.00 ml/kg to >3200 mg/kg in mice. The reported ip LD50
of other methacrylates used in the nail enhancement industry. values of Methacrylates were 1.110 ml/kg to 3900 mg/kg in rats
The ethyl methacrylate system may contain up to 10% of other and 0.497 ml/kg to 2889 mg/kg in mice. The reported dermal
methacrylates. (ABA and NMC 2001a and ABA 2001b). LD50 values of Methacrylates were >10 ml/kg to >3000 mg/kg
in rabbits and >20 ml/kg in guinea pigs. The reported inhalation
Occupational Exposure LC50 values of Methacrylates were 29 mg/l to 28,469 mg/m3 in
rats and >17.01 mg/l to 29.74 mg/l in mice. An intravenous dose
Cautilli and Hozack (1994) performed an in vitro analysis,
of 1.24 ml of 3344 × 10−6 M Lauryl Methacrylate was rapidly
which encompassed a 26 minute sampling time of cement re-
fatal to dogs.
moval fumes from a section of bovine femur and detected peak
In a 28-day inhalation study on rats, Butyl Methacrylate
levels of Butyl Methacrylate. Collecting pumps, placed adja-
caused upper airway irritation; the NOEL was 1801 mg/m3 .
cent to the working area, enabled collection of maximum sam-
In a 28-day oral toxicity study on rats, t-Butyl Methacrylate had
ple concentrations. A quantitative analysis was not performed
a NOEL of 20 mg/kg/day. A 45-day oral toxicity study on rats
in this phase.
reported Butyl Methacrylate had a NOEL of 30 mg/kg/day in
Another phase performed a quantitative analysis of fumes
males and 300 mg/kg/day in females. A 50-day oral toxicity
generated by ultrasonic removal of cement during revision
study on rats reported HEMA had a NOEL of <30 mg/kg/day
hip surgery. Samples were collected by industrial hygienists
in males and 30 mg/kg/day in females. Rats were exposed to
from the National Institute for Occupational Safety and Health
a saturated solution of Lauryl Methacrylate for twenty, 6-hour
(NIOSH) over two consecutive days during two hip surgeries.
exposure periods. No toxic signs were observed and necropsy
Butyl Methacrylate was not present at detectable levels during
was normal.
this second phase (Cautilli and Hozack 1994).
In a subchronic oral toxicity study, Beagle dogs were dosed
In its workplace exposure guide, the American Industrial
with 0.2 to 2.0 g/kg/day of C12 to C18 Methacrylate monomers
Hygiene Association (1981) stated that Trimethylolpropane
for 13 weeks. Hematology, biochemistry, and urine analy-
Trimethacrylate has a recommended workplace environmental
ses were comparable between controls and test groups. Only
exposure level (WEEL) of 1 mg/m3 (8-hour time weighted av-
the highest dose group had effects such as weight loss, eme-
erage for a 40-hour week).
sis, diarrhea, mucoid feces, or salivation observed. In another
study, rats were fed the C12 to C18 Methacrylate monomers
SUMMARY at concentrations between 5000 to 50,000 ppm for 13 weeks.
This report reviews the safety of a large number of Body weights, growth, and food consumption were signifi-
monomethacrylates, dimethacrylates, and trimethacrylates that cantly decreased in the highest dose group. Hematological, bio-
are known to be used in nail enhancement products. Only chemical, and urine analyses were comparable between test
Tetrahydrofurfuryl Methacrylate was reported to the FDA to groups and controls. Kidney and liver weights were increased
be used in nail extender products. in the high dose group as compared to controls. Microscopic
The polymerization rates of Butyl Methacrylate; t- examination of tissues did not reveal any compound-related
Butyl Methacrylate; Cyclohexyl Methacrylate; Ethoxyethyl lesions.
Methacrylate; 2-Ethoxy Ethoxy Ethyl Methacrylate; Ethy- There were few chronic toxicity studies on Methacrylates
lene Glycol Dimethacrylate; Hexyl Methacrylate; HEMA; found in the published literature. Therefore, data on methyl
Di-HEMA Trimethylhexyl Dicarbamate; Hydroxyethyl- methacrylate was used in the report. A chronic toxicity study
methacrylate Acetoacetate; Hydroxypropyl Methacrylate; in rats and hamsters exposed to methyl methacrylate at up to
Isobornyl Methacrylate; Isobutyl Methacrylate; Isopropyli- 400 ppm (6 h/day, 5 days/week) did not cause tumors in ham-
denediphenyl Bisglycidyl Methacrylate; Lauryl Methacrylate; sters or rats.
Methoxydiglycol Methacrylate; PEG-4 Dimethacrylate; Butyl Methacrylate (0.1 M) and Isobutyl Methacrylate
Pyromellitic Glycidyl Dimethacrylate; Tetrahydrofurfuryl (0.1 M) are mildly irritating to the rabbit eye. HEMA is corrosive
96 COSMETIC INGREDIENT REVIEW

when instilled in the rabbit eye, while PEG-4 Dimethacrylate and Ethyl methacrylate was tested in the L5178Y mouse lym-
Trimethylolpropane Trimethacrylate are minimally irritating. phoma cell assay. L5178Y/TK+/− cells were treated with 900-
The dermal irritation caused by Methacrylates has been 2100 μg/ml of ethyl methacrylate without exogenous activation
documented in guinea pigs and rabbits. Undiluted or high for 4 h and incubation lasted 9 to 11 days. Control cells were
concentration Methacrylates are typically moderate irritants treated with the solvent (dimethylsulfoxide) alone. Cytotoxic-
that can result in erythema and/or edema. Lower concentra- ity was observed at concentrations greater than 1000 μg/ml and
tion Methacrylates are typically mild or slightly irritating. The toxicity plateaued at concentrations above 1500 μg/ml, where
Methacrylates PII ranged from 0.08 to 5.6, depending on which survival fluctuated from 2 to 37%. A weak positive response
Methacrylate was tested and whether the site was abraded or was observed in cultures with 10–20% survival (1450, 1500,
intact skin. 1550, and 1626 μg/ml). The greatest number of aberrations oc-
The sensitizing potential of the Methacrylates has been a curred at a concentration of 1626 μg/ml (16% survival); ethyl
major concern regarding their safety in artificial nail systems. methacrylate induced 83 mutants/106 survivors and 11 aberra-
Results from several studies showed that HEMA , Isopropyli- tions/200 cells. Some of the cultures with less than 10% survival
denediphenyl Bisglycidyl Methacrylate, Lauryl Methacrylate, had mutation frequencies three times greater than background.
and Trimethylolpropane Trimethacrylate are strong sensitizers The colony size distribution was difficult to determine; however,
in guinea pigs. Butyl Methacrylate, Cyclohexyl Methacrylate, the researchers noted that cultures with mutation frequencies of
Hexyl Methacrylate, and Urethane Methacrylate are moderate 200 mutants/106 survivors (less than 10% survival) had an in-
sensitizers in guinea pigs. Hydroxypropyl Methacrylate is a duction of primarily small colonies. The researchers suggested
weak sensitizer in guinea pigs. PEG-4 Dimethacrylate and Tri- that the genotoxicity of Ethyl Methacrylate was likely due to a
ethylene Glycol Dimethacrylate are not considered sensitizers clastogenic mechanism.
in guinea pigs. Ethylene Glycol Dimethacrylate was not a sen- Ethylene Glycol Dimethacrylate, Isopropylidene-
sitizer in a study using guinea pigs, but was a strong sensitizer diphenyl Bisglycidyl Methacrylate, and Trimethylol propane
in another. Some test data has shown there is cross-reactivity Trimethacrylate were weakly positive in the L5178Y mouse
between various Methacrylates. lymphoma cell assay with metabolic activation. PEG-4
The effects of Butyl Methacrylate, HEMA, Hydroxypropyl Dimethacrylate and Trimethylolpropane Trimethacrylate were
Methacrylate, and Trimethylolpropane Trimethacrylate on the weakly positive in the L5178Y mouse lymphoma cell assay
reproductive parameters and/or the developmental parameters without metabolic activation.
of the offspring of rats were evaluated. Rats were dosed for 9 to Chronic dermal exposure of mice to PEG-4 Dimethacry-
49 days. The Butyl Methacrylate NOEL was 1000 mg/kg/day late (25 mg, 2× weekly for 80 weeks) or Trimethylolpropane
in parental males and 300 mg/kg/day in parental females; there Trimethacrylate (25 mg, 2× weekly for 80 weeks) did not result
were no effects on any reproductive parameters in males or de- in increased incidence of skin or visceral tumors. The carcino-
velopmental parameters in offspring. The HEMA NOEL was genicity of Triethylene Glycol Dimethacrylate (5, 25, or 50%)
1000 mg/kg/day (maximum dose tested) in both sexes and in the was assessed in a skin painting study (50 μl for 5 days/week for
developing pups. The Hydroxypropyl Methacrylate NOEL was 78 weeks) using mice. The NOEL was 5% Triethylene Glycol
1000 mg/kg/day (maximum dose tested) in both sexes and in the Dimethacrylate, but Triethylene Glycol Dimethacrylate did not
developing pups. Trimethylolpropane Trimethacrylate caused induce carcinogenicity at any dose level tested.
fetotoxic effects such as increased resorptions (mean incidence Due to the absence of carcinogenicity data on Methacrylates,
25.4%), decreased fetal viability (mean survival 74.6%), de- data on methyl methacrylate has been considered. In 1994, the
creased fetal weights, and decreased fetal lengths at a dose of IARC working group concluded that there is inadequate evi-
2500 mg/kg/day. dence in humans for the carcinogenicity of methyl methacrylate
The threshold concentration for embryotoxic and teratogenic and there is evidence suggesting a lack of carcinogenicity in ex-
effects in rats exposed to Butyl Methacrylate via inhalation was perimental animals. Methyl methacrylate is not classifiable as
0.1 mg/m3 . to its carcinogenicity to humans.
Butyl Methacrylate, t-Butyl Methacrylate, HEMA, Hexyl A standard Draize test to assess contact sensitization po-
Methacrylate, Hydroxypropyl Methacrylate, Isobutyl Methacry- tential of 1% Butyl Methacrylate caused one positive reac-
late, Isopropylidenediphenyl Bisglycidyl Methacrylate, PEG-4 tion in 12 volunteers. Ethylene Glycol Dimethacrylate, HEMA,
Dimethacrylate, Triethylene Glycol Dimethacrylate, Trimethy- Isopropylidenediphenyl Bisglycidyl Methacrylate, Triethylene
lolpropane Trimethacrylate, and Di-HEMA Trimethylhexyl Di- Glycol Dimethacrylate, and Di-HEMA Trimethylhexyl Dicar-
carbamate were not mutagenic in multiple Ames tests (using bamate were considered to be capable of causing hypersensitiv-
Salmonella typhimurium strains TA97, TA98, TA100, TA1535, ity/allergy in humans.
TA1537, and/or TA1538) both with and without metabolic Patients previously exposed to Methacrylate elicited pos-
activation. However, Butyl Methacrylate, Ethylene Glycol itive reactions to patch tests with concentrations as low as
Dimethacrylate in one test using Salmonella typhimurium strain 1% Butyl Methacrylate, 2% Ethylene Glycol Dimethacry-
TA1538 with metabolic activation was mutagenic. late, 0.02% HEMA, 0.02% Hydroxypropyl Methacrylate, 1%
 ESTER MONOMERS USED IN NAIL ENHANCEMENT PRODUCTS 97

Isobutyl Methacrylate, 0.0002% Isopropylidenediphenyl Bis- Andrews, L. S. and J. J. Clary. 1986. Review of the toxicity of multifunctional
glycidyl Methacrylate, 2% Tetrahydrofurfuryl Methacrylate, acrylates. J Toxicol Environ Health 19: 149–164.
2% Triethylene Glycol Dimethacrylate, 0.02% Di-HEMA American Industrial Hygiene Association. 1981. Workplace environmental ex-
posure level guide: trimethylolpropane trimethacrylate. Am. Ind. Hyg. Assoc.
Trimethylhexyl Dicarbamate. Most of these patients were em- J. 42: B-51–B-52.
ployed in dentistry or were artificial nail technicians. Assessment Technologies, Inc. 1994. An environmental fate and ecotoxicology
assessment of several methacrylic acid esters, with cover letter dated 06/16/94.
NTIS Report No. OTS0557437.
DISCUSSION Assessment Technologies, Inc. 1996. Methacrylates: an environmental assess-
The Expert Panel was concerned about the strong sensiti- ment. NTIS Report No. OTS0558768.2
zation and cross- or co-reactivity potential of the Methacry- Autian, J. 1975. Structure-toxicity relationships of acrylic monomers. Environ.
lates reviewed in this report. Animal studies indicated that most Health. Perspect. 11:141–52.
Benson, W. H., and R. A. Stackhouse. 1986. Evaluation of a new approach to
Methacrylates are moderate to strong sensitizers. However, the
the safety assessment of biomaterials. Drug. Chem. Toxicol. 9:275–84.
Panel received data that showed the rates of polymerization of Biodynamics Inc. 1981. Initial submission: an acute intraperitoneal toxicity
these Methacrylates were similar to that of ethyl methacrylate study of trimethylolpropane trimethacrylate in rats with cover letter dated
(the primary monomer used) and there would be little monomer 090492. NTIS Report No. OTS0571319.
available for exposure to the skin. Genotoxicity data indicated Björkner, B. 1980a. Allergenicity of trimethylol propane trimethacrylate in
ultraviolet curing inks in the guinea pig. Acta. Derm. Venerol. 60:528–
that some Methacrylates could produce chromosome damage in
531.
mammalian cells. In consideration of all these data, the Panel Björkner, B. 1980b. Contact allergy to 2-hydroxypropyl methacrylate (2-HPMA)
decided that these Methacrylates should be restricted to the nail in an ultraviolet curable ink. Acta. Derm. Venerol. 64:264–267.
and must not be in contact with the skin. Björkner, B., B. Niklasson, and K. Persson. 1984a. The sensitizing potential of
There was some concern that the exotherms created from the di-(meth)acrylates based on bisphenol A or epoxy resin in the guinea pig.
Contact. Derm. 10:286–304.
monomers rapid polymerization could damage the nail. Test data
Björkner, B. 1984b. Sensitizing potential of urethane (meth)acrylates in the
showed 50% polymerization in 3 to 4 minutes at 5% concentra- guinea pig. Contact. Derm. 11:115–119.
tions. However, the products do not produce significant levels Björkner, B. 1984c. The sensitizing capacity of multifunctional acrylates in the
of exotherms and clients rarely notice a slight warming of the guinea pig. Contact. Derm. 11:236–246.
nail during application. Bong, J. L., and J. S. C. English. 2000. Allergic contact dermatitis from airborne
exposure to acrylates. Contact. Derm. 43:242.
Bouillaguet, S., J. C. Wataha, M. Virgillito, L. Gonzalez, D. R. Rakich, and J.-M.
CONCLUSION Meyer. 2000. Effect of sub-lethal concentrations of HEMA (2-hydroxyethyl
Based on the available data, the CIR Expert Panel methacrylate) on THP-1 human monocyte-macrophages, in vitro.Dent. Mater.
16:213–217.
concluded that Butyl Methacrylate; t-Butyl Methacrylate; British Petroleum Company. 1981. Initial submission: irritation and mutagenic-
Cyclohexyl Methacrylate; Ethoxyethyl Methacrylate; 2-Ethoxy ity tests of hydroxyethyl methacrylate and related studies with cover letter
Ethoxy Ethyl Methacrylate; Ethylene Glycol Dimethacrylate; dated 082892. NTIS Report No. OTS0556083.
Hexyl Methacrylate; HEMA; Di-HEMA Trimethylhexyl Brixham Environmental Lab. 1992. N-butyl methacrylate: determination of oc-
Dicarbamate; Hydroxyethylmethacrylate Acetoacetate; Hy- tanol water partition coefficient. NTIS Report No. OTS0537781.
Bushy Run Research Center. 1995. Initial submission: draft report, triethylene
droxypropyl Methacrylate; Isobornyl Methacrylate; Isobutyl glycol dimethacrylate-carcinogenesis skin painting study in male mice, with
Methacrylate; Isopropylidenediphenyl Bisglycidyl Methacry- cover letter dated 06/26/95. NTIS Report No. OTS0557901.
late; Lauryl Methacrylate; Methoxydiglycol Methacrylate; Cameron, T. P., A. M. Rogers-Back, T. E. Lawlor, J. W. Harbell, H. E. Seifried,
PEG-4 Dimethacrylate; Pyromellitic Glycidyl Dimethacry- and V. C. Dunkel. 1991. Genotoxicity of multifunctional acrylates in the
late;Tetrahydrofurfuryl Methacrylate; Triethylene Glycol Salmonella/mammalian-microsome assay and mouse lymphoma TK+/− as-
say. Environ. Mol. Mutagen. 17:264-271.
Dimethacrylate; Trimethylol propane Trimethacrylate; and G. P. Cautilli, and W. J. Hozack. 1994. Analysis of fume emission from ultrasonic
Urethane Methacrylate are safe as used in nail enhancement removal of methyl methacrylate cement in revision hip surgery. Journal of
products when skin contact is avoided. Products containing these Arthroplasty 9:305–306.
ingredients should be accompanied with directions to avoid skin ChemID. 2000. Butyl Methacrylate and Lauryl Methacrylate entries. ChemID.
contact, because of the sensitizing potential of Methacrylates. database. Bethesda, MD: National Library of Medicine.
ChemIDplus. 2001. Isobutyl Methacrylate entry. ChemID. database. Bethesda,
MD: National Library of Medicine.
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American Beauty Association/Nail Manufacturers Council (ABA/NMC). 1991. Cytotoxic effects of residual chemicals from polymeric biomaterials
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