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The Cosmetic Ingredient Review Expert Panel assessed the safety of bis-diglyceryl polyacyladipate-2 and bis-diglyceryl polyacyladipate-1 as used in cosmetics, finding that these ingredients are safe in cosmetic formulations in the present practices of use and concentration. Both ingredients are lanolin substitutes and are reported to function in cosmetics as skin-conditioning agents--emollients. The Panel reviewed available animal and clinical data in making its determination of safety.

The Cosmetic Ingredient Review (CIR) Expert Panel assessed the safety of silica silylate, silica dimethyl silylate, trimethylsiloxysilicate, and trifluoropropyldimethyl/trimethylsiloxysilicate as used in cosmetics. These silylates and surface-modified siloxysilicates function in cosmetics as antifoaming agents, anticaking agents, bulking agents, binders, skin-conditioning agents--emollient, skin-conditioning agents-occlusive, slip modifiers, suspension agents--nonsurfactant, and viscosity increasing agents--nonaqueous. The Expert Panel reviewed the available animal and clinical data as well as information from a previous CIR safety assessment of amorphous silica. The CIR Expert Panel concluded that silica silylate, silica dimethyl silylate, trimethylsiloxysilicate, and trifluoropropyldimethyl/trimethylsiloxysilicate are safe as used when formulated and delivered in the final product not to be irritating or sensitizing to the respiratory tract.

Cocamide diethanolamine (DEA) and some of the other diethanolamides are mainly used as surfactant foam boosters or viscosity increasing agents in cosmetics, although a few are reported to be used as hair and skin conditioning agents, surfactant-cleansing or surfactant-emulsifying agents, or as an opacifying agent. The Cosmetic Ingredient Review (CIR) Expert Panel considered new data and information from previous CIR reports to assess the concerns about the potential for amidases in human skin to convert these diethanolamides into DEA and the corresponding fatty acids. The Expert Panel concluded that these diethanolamides are safe as used when formulated to be nonirritating and when the levels of free DEA in the diethanolamides do not exceed those considered safe by the Panel. The Panel also recommended that these ingredients not be used in cosmetic products in which N-nitroso compounds can be formed.

The Cosmetic Ingredient Review Expert Panel assessed the safety of triethanolamine (TEA) and 31 related TEA-containing ingredients as used in cosmetics. The TEA is reported to function as a surfactant or pH adjuster; the related TEA-containing ingredients included in this safety assessment are reported to function as surfactants and hair- or skin-conditioning agents. The exception is TEA-sorbate, which is reported to function as a preservative. The Panel reviewed the available animal and clinical data. Although data were not available for all the ingredients, the panel relied on the information available for TEA in conjunction with previous safety assessments of components of TEA-containing ingredients. These data could be extrapolated to support the safety of all included ingredients. The panel concluded that TEA and related TEA-containing ingredients named in this report are safe as used when formulated to be nonirritating. These ingredients should not be used in cosmetic products in which N-nitroso compounds can be formed.

2-Amino-4-hydroxyethylaminoanisole and its salt, 2-amino-4-hydroxyethylaminoanisole sulfate, are used as coupling agents in oxidative hair dyes. The Cosmetic Ingredient Review Expert Panel reviewed relevant animal and human data related to the ingredient. The Expert Panel concluded that 2-amino-4-hydroxyethylaminoanisole and 2-amino-4-hydroxyethylaminoanisole sulfate are safe for use in oxidative hair dye formulations. The Expert Panel cautioned that these ingredients should not be used in cosmetic products in which N-nitroso compounds may be formed.

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

The functions of alkyl benzoates in cosmetics include fragrance ingredients, skin-conditioning agents--emollient, skin-conditioning agents--miscellaneous, preservatives, solvents, and plasticizers. The Cosmetic Ingredient Review Expert Panel reviewed the relevant animal and human data and noted gaps in the available safety data for some of the alkyl benzoates. Similar structure activity relationships, biologic functions, and cosmetic product usage allowed the available data of many of the alkyl benzoates to be extended to the entire group. Carcinogenicity data were not available, but available data indicated that these alkyl benzoate cosmetic ingredients are not genotoxic. Also benzoic acid and tested component alcohols were not reproductive or developmental toxicants, are not genotoxic in almost all assays, and are not carcinogenic. These ingredients were determined to be safe in the present practices of use and concentration.

Quaternary ammonium salts, including alkyl chain, alkanol, and polymer derivatives (trimoniums) are used in cosmetics mainly as surfactant-cleansing agents, hair-conditioning agents, and antistatic agents.  The Cosmetic Ingredient Review Expert Panel reviewed the relevant animal and human data and noted gaps in the available safety data for some of the trimomiums.  The available data on many of the trimoniums are sufficient, however, and similar structural activity relationships, functions in cosmetics, and cosmetic product usage supported extending these data to the entire group.  These ingredients were determined to be safe in the present practices of use and concentration when formulated to be nonirritating.

The CIR Expert Panel assessed the safety of Alkyl PEG Ethers as used in cosmetics. These ingredients primarily function in cosmetics as surfactants, and some have additional functions as skin-conditioning agents, fragrance ingredients, and emulsion stabilizers. The Panel reviewed available relevant animal and clinical data, as well as information from previous CIR reports; when data were not available for individual ingredients, the Panel extrapolated from the existing data to support safety. The Panel concluded that the Alkyl PEG ethers are safe as used when formulated to be nonirritating, and the same applies to future alkyl PEG ether cosmetic ingredients that vary from those ingredients recited herein only by the number of ethylene glycol repeat units.

Stearyl heptanoate is an ester of stearyl alcohol and heptanoic acid that functions in cosmetics as a skin conditioning agent and is in the general class of chemicals called stearyl alkanoates. Stearyl caprylate, stearyl palmitate, stearyl stearate, stearyl behenate, and stearyl olivate are stearyl alkanoates with similar chemical structures, toxicokinetics, and functions in cosmetics. These water-insoluble stearyl alkanoates, when metabolized, yield stearyl alcohol and a corresponding fatty acid. The available information supports the safety of all of the related stearyl alkanoates. The Expert Panel concluded that stearyl heptanoate, stearyl caprylate, stearyl palmitate, stearyl stearate, stearyl behenate, and stearyl olivate are safe in the present practices of use and concentration.

Caprylyl glycol and related 1,2-glycols are used mostly as skin and hair conditioning agents and viscosity agents in cosmetic products, and caprylyl glycol and pentylene glycol also function as cosmetic preservatives. The Cosmetic Ingredient Review (CIR) Expert Panel noted that, while these ingredients are dermally absorbed, modeling data predicted decreased skin penetration of longer chain 1,2-glycols. Because the negative oral toxicity data on shorter chain 1,2-glycols and genotoxicity data support the safety of the 1,2-glycols reviewed in this safety assessment, the Panel concluded that these ingredients are safe in the present practices of use and concentration described in this safety assessment.

Propylene glycol is an aliphatic alcohol that functions as a skin conditioning agent, viscosity decreasing agent, solvent, and fragrance ingredient in cosmetics. Tripropylene glycol functions as a humectant, antioxidant, and emulsion stabilizer. Polypropylene glycols (PPGs), including PPG-3, PPG-7, PPG-9, PPG-12, PPG-13, PPG-15, PPG-16, PPG-17, PPG-20, PPG-26, PPG-30, PPG-33, PPG-34, PPG-51, PPG-52, and PPG-69, function primarily as skin conditioning agents, with some solvent use. The majority of the safety and toxicity information presented is for propylene glycol (PG). Propylene glycol is generally nontoxic and is noncarcinogenic. Clinical studies demonstrated an absence of dermal sensitization at use concentrations, although concerns about irritation remained. The CIR Expert Panel determined that the available information support the safety of tripropylene glycol as well as all the PPGs. The Expert Panel concluded that PG, tripropylene glycol, and PPGs ≥3 are safe as used in cosmetic formulations when formulated to be nonirritating.

Alkyl acetates, as well as acetic acid and acetate salts, are widely used cosmetic ingredients, with a wide range of functions as fragrances, solvents, or skin-conditioning agents, depending on the specific ingredient. Available data on alkyl acetates, and acetic acid and the alcohol to which they could be metabolized, were considered adequate to support the safety of the entire group in the present practices of use and concentration in cosmetics.

The CIR Expert Panel assessed the safety of dicarboxylic acids and their salts and esters as used in cosmetics. Most dicarboxylic acids function in cosmetics as pH adjusters or fragrance ingredients, but the functions of most of the salts in cosmetics are not reported. Some of the esters function as skin conditioning or fragrance ingredients, plasticizers, solvents, or emollients. The Expert Panel noted gaps in the available safety data for some of the dicarboxylic acid and their salts and esters in this safety assessment. The available data on many of the ingredients are sufficient, however, and similar structural activity relationships, biologic functions, and cosmetic product usage suggest that the available data may be extrapolated to support the safety of the entire group. The Panel concluded that the ingredients named in this report are safe in the present practices of use and concentration.

Cocamidopropyl betaine (CAPB) and related amidopropyl betaines are zwitterions used mainly as surfactants in cosmetics. These cosmetic ingredients are similar in their chemistry, in particular with respect to the presence of 3,3-dimethylamino-propylamine (DMAPA) and fatty acid amidopropyl dimethylamine (amidoamine) impurities, which are known as sensitizers. The CIR Expert Panel concluded that because these ingredients present no other significant toxicity, when formulated to be nonsensitizing (which may be based on a quantitative risk assessment), these ingredients are safe for use as cosmetic ingredients in the practices of use and concentration of this safety assessment.

Xylene sulfonic acid, toluene sulfonic acid, and alkyl aryl sulfonate hydrotropes used in cosmetics as surfactants, hydrotropes, were reviewed in this safety assessment. The similar structure, properties, functions, and uses of these ingredients enabled grouping them and using the available toxicological data to assess the safety of the entire group. The Cosmetic Ingredient Review Expert Panel reviewed relevant animal and human data related to these ingredients. The panel concluded that xylene sulfonic acid and alkyl aryl sulfonate hydrotropes are safe as cosmetic ingredients in the present practices of use and concentrations as described in this safety assessment, when formulated to be nonirritating.

Pelargonic acid and its esters function as skin-conditioning agents in cosmetics. Molecular weight (mw) and octanol-water partition coefficient data suggest that dermal penetration is possible. The biohandling of branched-chain fatty acids is not the same as for straight-chain fatty acids, but the differences are not significant to the conclusion that they all are readily metabolized to nontoxic moieties. Limited data suggested that the penetration of other ingredients may be enhanced if these ingredients are present in the same formulation. These ingredients are not significant oral or dermal toxicants in animal studies. They are not reproductive/developmental toxicants or genotoxic/carcinogenic in animal studies. The available data suggested that product formulations containing these ingredients would be nonirritating and nonsensitizing to human skin, but formulators were cautioned to consider the penetration enhancement potential. The Cosmetic Ingredient Review (CIR) Expert Panel concluded that these ingredients are safe in the present practices of use and concentration.

Cyclomethicone (mixture) and the specific chain length cyclic siloxanes (n = 4-7) reviewed in this safety assessment are cyclic dimethyl polysiloxane compounds. These ingredients have the skin/hair conditioning agent function in common. Minimal percutaneous absorption was associated with these ingredients and the available data do not suggest skin irritation or sensitization potential. Also, it is not likely that dermal exposure to these ingredients from cosmetics would cause significant systemic exposure. The Cosmetic Ingredient Review Expert Panel concluded that these ingredients are safe in the present practices of use and concentration.

Polyvinyl methyl ether/maleic acid (PVM/MA) copolymer, and its related salts and esters, are used in cosmetics, mainly as binders, film formers, and hair fixatives. Animal and human data relevant to the use of these ingredients in cosmetic products were reviewed by the CIR Expert Panel. The Panel concluded that these ingredients are safe for use in cosmetic products.

Polymethyl methacrylate (PMMA) and related cosmetic ingredients methyl methacrylate crosspolymer and methyl methacrylate/glycol dimethacrylate crosspolymer are polymers that function as film formers and viscosity-increasing agents in cosmetics. The Food and Drug Administration (FDA) determination of safety of PMMA use in several medical devices, which included human and animal safety data, was used as the basis of safety of PMMA and related polymers in cosmetics by the Cosmetic Ingredient Review (CIR) Expert Panel.  The PMMA used in cosmetics is substantially the same as in medical devices.  The Panel concluded that these ingredients are safe as cosmetic ingredients in the practices of use and concentrations as described in this safety assessment.

Sesamum indicum (sesame) seed oil and related cosmetic ingredients are derived from Sesamum indicum. Sesamum indicum (sesame) seed oil, sesamum indicum (sesame) oil unsaponifiables, and hydrogenated sesame seed oil function as conditioning agents. Sodium sesameseedate functions as a cleansing agent, emulsifying agent, and a nonaqueous viscosity increasing agent. These ingredients are neither skin irritants, sensitizers, teratogens, nor carcinogens at exposures that would result from cosmetic use. Both animal and human data relevant to the cosmetic use of these ingredients were reviewed. The CIR Expert Panel concluded that these ingredients are safe in the present practices of use and concentration as described in this safety assessment.

Many cosmetic ingredients are derived from Zea mays (corn). While safety test data were not available for most ingredients, similarities in preparation and the resulting similar composition allowed extrapolation of safety data to all listed ingredients. Animal studies included acute toxicity, ocular and dermal irritation studies, and dermal sensitization studies. Clinical studies included dermal irritation and sensitization. Case reports were available for the starch as used as a donning agent in medical gloves. Studies of many other endpoints, including reproductive and developmental toxicity, use corn oil as a vehicle control with no reported adverse effects at levels used in cosmetics. While industry should continue limiting ingredient impurities such as pesticide residues before blending into a cosmetic formulation, the CIR Expert Panel determined that corn-derived ingredients are safe for use in cosmetics in the practices of use and concentration described in the assessment.

Cocos nucifera (coconut) oil, oil from the dried coconut fruit, is composed of 90% saturated triglycerides. It may function as a fragrance ingredient, hair conditioning agent, or skin-conditioning agent and is reported in 626 cosmetics at concentrations from 0.0001% to 70%. The related ingredients covered in this assessment are fatty acids, and their hydrogenated forms, corresponding fatty alcohols, simple esters, and inorganic and sulfated salts of coconut oil. The salts and esters are expected to have similar toxicological profiles as the oil, its hydrogenated forms, and its constituent fatty acids. Coconut oil and related ingredients are safe as cosmetic ingredients in the practices of use and concentration described in this safety assessment.

Kojic acid functions as an antioxidant in cosmetic products. Kojic acid was not a toxicant in acute, chronic, reproductive, and genotoxicity studies. While some animal data suggested tumor promotion and weak carcinogenicity, kojic acid is slowly absorbed into the circulation from human skin and likely would not reach the threshold at which these effects were seen. The available human sensitization data supported the safety of kojic acid at a use concentration of 2% in leave-on cosmetics. Kojic acid depigmented black guinea pig skin at a concentration of 4%, but this effect was not seen at 1%. The Cosmetic Ingredient Review (CIR) Expert Panel concluded that the 2 end points of concern, dermal sensitization and skin lightening, would not be seen at use concentrations below 1%; therefore, this ingredient is safe for use in cosmetic products up to that level.

Hydroquinone is an aromatic compound that functions in cosmetics as an antioxidant, fragrance, reducing agent, or polymerization inhibitor. Hydroquinone is also used as a skin bleaching agent. Safety and toxicity information indicate that hydroquinone is dermally absorbed in humans from both aqueous and alcoholic formulations and is excreted mainly as the glucuronide or sulfate conjugates. Hydroquinone is associated with altered immune function in vitro and in vivo in animals and an increased incidence of renal tubule cell tumors and leukemia in F344 rats, but the relevance to humans is uncertain. Quantitatively, however, the use of hydroquinone in cosmetics is unlikely to result in renal neoplasia through this mode of action. Thus, hydroquinone is safe at concentrations of ≤1% in hair dyes and is safe for use in nail adhesives. Hydroquinone should not be used in other leave-on cosmetics.

Calendula officinalis extract, C officinalis flower, C officinalis flower extract, C officinalis flower oil, and C officinalis seed oil are cosmetic ingredients derived from C officinalis. These ingredients may contain minerals, carbohydrates, lipids, phenolic acids, flavonoids, tannins, coumarins, sterols and steroids, monoterpenes, sesquiterpenes, triterpenes, tocopherols, quinones, amino acids, and resins. These ingredients were not significantly toxic in single-dose oral studies using animals. The absence of reproductive/developmental toxicity was inferred from repeat-dose studies of coriander oil, with a similar composition. Overall, these ingredients were not genotoxic. They also were not irritating, sensitizing, or photosensitizing in animal or clinical tests but may be mild ocular irritants. The Cosmetic Ingredient Review (CIR) Expert Panel concluded that these ingredients are safe for use in cosmetics in the practices of use and concentration given in this amended safety assessment.

Sodium dodecylbenzenesulfonate is one of a group of salts of alkylbenzene sulfonates used in cosmetics as surfactant-cleansing agents. Sodium dodecylbenzenesulfonate is soluble in water and partially soluble in alcohol, with dermal absorption dependent on pH. Dodecylbenzenesulfonate salts are not toxic in single-dose oral and dermal animal tests, and no systemic toxicities were observed in repeat-dose dermal animal studies. In dermal animal studies, no evidence of reproductive or developmental toxicity was reported. At 15% concentrations, sodium dodecylbenzenesulfonate was severely irritating to rabbit skin. The Cosmetic Ingredient Review Expert Panel concluded that the irritant properties of these ingredients are similar to those of other detergents, with severity dependent on concentration and pH. Products containing these ingredients should be formulated to ensure that the irritancy potential is minimized.

Sodium laureth sulfate is a member of a group of salts of sulfated ethoxylated alcohols, the safety of which was evaluated by the Cosmetic Ingredient Review (CIR) Expert Panel for use in cosmetics. Sodium and ammonium laureth sulfate have not evoked adverse responses in any toxicological testing. Sodium laureth sulfate was demonstrated to be a dermal and ocular irritant but not a sensitizer. The Expert Panel recognized that there are data gaps regarding use and concentration of these ingredients. However, the overall information available on the types of products in which these ingredients are used and at what concentrations indicates a pattern of use. The potential to produce irritation exists with these salts of sulfated ethoxylated alcohols, but in practice they are not regularly seen to be irritating because of the formulations in which they are used. These ingredients should be used only when they can be formulated to be nonirritating.

Methylisothiazolinone (MIT) is a heterocyclic organic compound used as a preservative in cosmetics and personal care products in concentrations up to 0.01%. MIT is a colorless, clear liquid with a mild odor that is completely soluble in water; mostly soluble in acetonitrile, methanol, and hexane; and slightly soluble in xylene. Consistent with its solubility, dermal penetration is low. The Cosmetic Ingredient Review Expert Panel noted the in vitro evidence of neurotoxicity but concluded that the absence of any neurotoxicity findings in the many in vivo studies, including subchronic, chronic, and reproductive and developmental animal studies, suggests that MIT would not be neurotoxic as used in cosmetics. Although recognizing that MIT was a sensitizer in both animal and human studies, the panel concluded that there is a threshold dose response and that cosmetic products formulated to contain concentrations of MIT at 100 ppm (0.01%) or less would not be expected to pose a sensitization risk. Accordingly, MIT may be safely used as a preservative in cosmetics up to that concentration.

Dilauryl thiodipropionate (DLTDP), dicetyl thiodipropionate, dimyristyl thiodipropionate, distearyl thiodipropionate, and ditridecyl thiodipropionate are dialkyl esters of their respective alcohols and thiodipropionic acid (TDPA) used in cosmetics. Ingested DLTDP was excreted in the urine as TDPA. Single-dose acute oral and parenteral studies and subchronic and chronic repeated dose oral studies did not suggest significant toxicity. Neither DLTDP nor TDPA was irritating to animal skin or eyes and they were not sensitizers. TDPA was neither a teratogen nor a reproductive toxicant. Genotoxicity studies were negative for TDPA and DLTDP. Clinical testing demonstrated some evidence of irritation but no sensitization or photosensitization. The Cosmetic Ingredient Review Expert Panel considered that the data from DLTDP reasonably may be extrapolated to the other dialkyl esters and concluded that these ingredients were safe for use in cosmetic products that are formulated to be nonirritating.

This report addresses the safety of the inorganic salts and esters of various fatty alcohols of myristic acid. Most of the esters are used as skin conditioning agents in many types of cosmetics in a range of concentrations. Myristate esters are readily hydrolyzed to the corresponding alcohols and acids, which are then further metabolized. Myristate salts readily dissociate in any likely cosmetic formulation. The Cosmetic Ingredient Review (CIR) Panel recognized that much of the data supporting the ingredients in this group were previously reviewed in safety assessments for related ingredients. Where specific data did not exist, the Panel considered structure-activity relationships in determining the safety of these ingredients as used in cosmetics. The Panel determined that myristic acid and its salts and esters are safe as cosmetic ingredients in the current practices of use and concentration.

Sodium cetearyl sulfate is the sodium salt of a mixture of cetyl and stearyl sulfate. The other ingredients in this safety assessment are also alkyl salts, including ammonium coco-sulfate, ammonium myristyl sulfate, magnesium coco-sulfate, sodium cetyl sulfate, sodium coco/hydrogenated tallow sulfate, sodium coco-sulfate, sodium decyl sulfate, sodium ethylhexyl sulfate, sodium myristyl sulfate, sodium oleyl sulfate, sodium stearyl sulfate, sodium tallow sulfate, sodium tridecyl sulfate, and zinc coco-sulfate. These ingredients are surfactants used at concentrations from 0.1% to 29%, primarily in soaps and shampoos. Many of these ingredients are not in current use. The Cosmetic Ingredient Review (CIR) Expert Panel previously completed a safety assessment of sodium and ammonium lauryl sulfate. The data available for sodium lauryl sulfate and ammonium lauryl sulfate provide sufficient basis for concluding that sodium cetearyl sulfate and related alkyl sulfates are safe in the practices of use and concentration described in the safety assessment.

Quaternium-15 is an antimicrobial agent used in cosmetics as a cosmetic preservative and antistatic agent. Little systemic toxicity was reported in most single-dose or repeated-dose animal studies. Quaternium-15 was an oral teratogen, but not a dermal teratogen, in rats at doses that exceeded the expected cumulative exposure from cosmetics. The frequency of sensitization increased in North America but not in Europe, where Quaternium-15 is used less often. In almost all animal and human studies, Quaternium-15 at 0.2% was not a sensitizer. The weight of evidence suggested that a 0.2% concentration is not a sensitizer and that cosmetic products containing Quaternium-15 up to that level are safe.

Allantoin is a heterocyclic organic compound. Allantoin ascorbate, allantoin biotin, allantoin galacturonic acid, allantoin glycyrrhetinic acid, allantoin panthenol, and allantoin polygalacturonic acid are complexes of allantoin. All of the ingredients in this review act as skin-conditioning agents. Allantoin was reported to be used in 1376 cosmetic products at concentrations up to 2%. There are data gaps regarding use and concentration of the remaining allantoin complexes. Ascorbic acid, biotin, glycyrrhetinic acid, and panthenol have been determined by the CIR Expert Panel to be safe. Galacturonic acid and polygalacturonic acid have not been reviewed by the CIR Expert Panel, and substantial data on these chemicals were not available. The safety test data in this safety assessment and in previous safety assessments were considered sufficient to support the safety of allantoin and the allantoin complexes in product categories and at concentrations reviewed in this safety assessment.

Toluene-2,5-diamine, toluene-2,5-diamine sulfate, and toluene-3,4-diamine are diaminotoluenes used as colorants in permanent hair dyes and tints. Toluene-2,5-diamine is used in 79 products at concentrations up to 3%; toluene-2,5-diamine sulfate is used in 168 products at concentrations up to 4%. Toluene-3,4-diamine does not appear to be in current use. Previously, the Cosmetic Ingredient Review Expert Panel determined that all 3 ingredients were safe for use as hair dyes. New data suggest that differences in toxicity, especially with respect to carcinogenicity, may exist as a function of placement of amine groups around the benzene ring. The Expert Panel concluded that toluene-2,5-diamine and toluene-2,5-diamine sulfate and are safe as hair dye ingredients in the present practices of use and concentrations but that there are insufficient data supporting the safety of toluene-3,4-diamine.

Sodium picramate is the sodium salt of picramic acid, a substituted phenolic compound. Sodium picramate and picramic acid function as hair colorants; they are reportedly used in 31 and 3 hair-dye products, respectively. No concentration-of-use data were available for sodium picramate, but picramic acid was reported to be used at 0.6%. The Cosmetic Ingredient Review Expert Panel recognized that adding picramic acid to a hair-dye formulation likely results in formation of a salt such as sodium picramate, which suggested that safety test data for one ingredient would be applicable to the other. Hair dyes containing these ingredients bear a caution statement and patch test instructions for determining whether the product causes skin irritation. The panel finds that the available data support the safety of these colorants in hair dyes and expects that sodium picramate would be used at concentrations comparable to those reported for picramic acid.

Piper methysticum leaf/root/stem extract is the cosmetic ingredient name for a material derived from the leaves, roots, and stems of the Piper methysticum G. Forster plant, commonly known as kava kava. This and other kava-derived ingredients are used as skin-conditioning agents at concentrations from 0.0001% to 0.1%. The Food and Drug Administration issued a consumer advisory in 2002 expressing concern about liver damage in individuals who have ingested kava products. The available oral toxicity data support the concern about liver damage on ingestion but do not resolve the question, for example, whether these ingredients would be substantially absorbed through the skin. Other data needs are described, including toxicology data for yangonin, methysticin, and kavain, which may be present in kava-derived ingredients. Accordingly, the available data are insufficient to support the safety of these ingredients in cosmetics.

2-Amino-3-nitrophenol, 2-amino-4-nitrophenol, 2-amino-5-nitrophenol, 4-amino-3-nitrophenol, 4-amino-2-nitrophenol, 2-amino-4-nitrophenol sulfate, 3-nitro-p-hydroxyethylaminophenol, and 4-hydroxypropylamino-3-nitrophenol are substituted aromatic compounds used as semipermanent (nonoxidative) hair colorants and as toners in permanent (oxidative) hair dye products. All ingredients in this group except 2-amino-4-nitrophenol sulfate, 2-amino-5-nitrophenol, and 4-amino-2-nitrophenol have reported uses in cosmetics at use concentrations from 2% to 9%. The available toxicity studies for these amino nitrophenol hair dyes did not suggest safety concerns except for the potential carcinogenicity and mutagenicity of 4-amino-2-nitrophenol. 2-Amino-3-nitrophenol, 2-amino-4-nitrophenol, 2-amino-4-nitrophenol sulfate, 2-amino-5-nitrophenol, 4-amino-3-nitrophenol, 3-nitro-p-hydroxyethylaminophenol, and 4-hydroxypropylamino-3-nitrophenol are safe as hair dye ingredients in the practices of use and concentration as described in this safety assessment, but the data are insufficient to make a safety determination for 4-amino-2-nitrophenol.

Tall oil acid is a mixture of oleic and linoleic acids (fatty acids) and rosin acids derived from tall oil, a by-product of pulp from resinous woods, used in cosmetic products as a surfactant at concentrations up to 8%. Ammonium, potassium, and sodium salts also are listed as cosmetic ingredients. In addition to the studies summarized in this report, extensive toxicity, genotoxicity, and carcinogenicity studies in animals are available for oleic, lauric, palmitic, myristic, and stearic fatty acids as published earlier by the Cosmetic Ingredient Review (CIR). These data may be extrapolated to tall oil acid and its salts. There are no reports of current uses or use concentration data for ammonium tallate, nor are use concentration data available for the other salts. The CIR Expert Panel found tall oil acid, ammonium tallate, potassium tallate, and sodium tallate to be safe cosmetic ingredients in the given practices of use and concentration.

PPG-2 methyl ether, PPG-3 methyl ether, and PPG-2 methyl ether acetate are used in cosmetics as fragrance ingredients and/or solvents at concentrations of 0.4% to 2%. Propylene glycol ethers are rapidly absorbed and distributed throughout the body when introduced by inhalation or oral exposure, but the inhalation toxicity of PPG-2 methyl ether vapor, for example, is low. Aerosols, such as found with hair sprays, produce particle sizes that are not respirable. Because these ingredients are highly water-soluble, they are likely to be absorbed through the human skin only at slow rates, resulting in low blood concentrations and rapid removal by the kidney. These ingredients are not genotoxic and are not reproductive or developmental toxicants. Overall the data are sufficient to conclude that PPG-2 methyl ether, PPG-3 methyl ether, and PPG-2 methyl ether acetate are safe as used in cosmetics.

Basic Violet 3, Basic Violet 1, and Basic Violet 4 are triphenylmethane dyes that function as direct (nonoxidative) hair colorants. No current uses or use concentrations in cosmetics are reported. The term Gentian Violet is used synonymously with Basic Violet 1 and Basic Violet 3, although the chemical structures of these 2 dyes are not the same. The Cosmetic Ingredient Review Expert Panel noted that Basic Violet 1, 3, and 4 contain quaternary ammonium ions, and therefore the rate of penetration across the epidermis is expected to be slow. The panel concluded that because of the carcinogenic potential of these dyes, insufficient data exist to support the safety of Basic Violet 1, 3, and 4 in cosmetic formulation. Dermal absorption data and a risk assessment are needed to complete this safety assessment.

Aminomethyl propanol and aminomethyl propanediol are substituted aliphatic alcohols that function as pH adjusters in cosmetic products at concentrations less than 10%; additionally, aminomethyl propanediol is a fragrance. Extensive oral toxicity data are reviewed, with fewer inhalation toxicity data. Dermal toxicity data are presented that demonstrate, for example, that a mascara with 1.92% aminomethyl propanediol does not cause dermal irritation or allergic contact sensitization, suggesting that the maximum reported use concentration of 2% in mascara would be safe. Although these ingredients are primary amines that are not substrates for N-nitrosation, they may contain secondary amines as impurities in finished products that may undergo N-nitrosation. These ingredients should not be included in cosmetic formulations containing N-nitrosating agents. The Cosmetic Ingredient Review Expert Panel concludes that aminomethyl propanol and aminomethyl propanediol are safe as cosmetic ingredients in the practices of use and concentrations as described in this safety assessment.

This safety assessment includes Ammonium and Glyceryl Thioglycolate and Thioglycolic Acid Butyl, Calcium, Ethanolamine, Ethyl, Isooctyl, Isopropyl, Magnesium, Methyl, Potassium, and Sodium Thioglycolate, as used in cosmetics. Thioglycolates penetrate skin and distribute to the kidneys, lungs, small intestine, and spleen; excretion is primarily in urine. Thioglycolates were slightly toxic in rat acute oral toxicity studies. Thioglycolates are minimal to severe ocular irritants. Thioglycolates can be skin irritants in animal and in vitro tests, and can be sensitizers. A no-observable-adverse-effect level for reproductive and developmental toxicity of 100 mg/kg per day was determined using rats. Thioglycolates were not mutagenic, and there was no evidence of carcinogenicity. Thioglycolates were skin irritants in some clinical tests. Clinically significant adverse reactions to these ingredients used in depilatories are not commonly seen, suggesting current products are formulated to be practically nonirritating under conditions of recommended use. Formulators should take steps necessary to assure that current practices are followed.

Hyaluronic acid, sodium hyaluronate, and potassium hyaluronate function in cosmetics as skin conditioning agents at concentrations up to 2%. Hyaluronic acid, primarily obtained from bacterial fermentation and rooster combs, does penetrate to the dermis. Hyaluronic acid was not toxic in a wide range of acute animal toxicity studies, over several species and with different exposure routes. Hyaluronic acid was not immunogenic, nor was it a sensitizer in animal studies. Hyaluronic acid was not a reproductive or developmental toxicant. Hyaluronic acid was not genotoxic. Hyaluronic acid likely does not play a causal role in cancer metastasis; rather, increased expression of hyaluronic acid genes may be a consequence of metastatic growth. Widespread clinical use of hyaluronic acid, primarily by injection, has been free of significant adverse reactions. Hyaluronic acid and its sodium and potassium salts are considered safe for use in cosmetics as described in the safety assessment.

Introduction: The most frequent mutation in human hepatocellular carcinoma (HCC) in populations exposed to a high dietary intake of aflatoxin B1 (AFB1) is a mutation in codon 249 of the p53 gene. Schistosomiasis is known to cause p53 mutation. We hypothesized that the combination of schistosomiasis and aflatoxin B1 increases the incidence of p53 gene mutation., Methods: Liver tissue from 21 patients with schistosomiasis and 5 patients without schistosomiasis were analyzed for occurrence of mutations of the p53 gene and levels of N7-guanine-AFB1 adducts., Results: The presence of mutations in codon 249 of p53 gene was higher in patients infected with Schistosoma haematobium (S. haematobium) than in those infected with Schistosoma mansoni (S. mansoni) or a combination of both strains (p < 0.01), compared to control subjects. No mutations were detected in p53 gene in liver DNA from schistosomiasis-free patients. Significant amounts of N7-guanine-AFB1 adducts and novel adenine-adducts (p < 0.01) were detected in patients with schistosomiasis, mostly in patients infected with S. haematobium or a combination of both strains, compared to control subjects., Conclusion: These data suggest that schistosomiasis and exposure to aflatoxin B1 act synergistically to increase the incidence of p53 gene mutation. The increase in p53 mutations may enhance progression of HCC at an early age in patients with schistosomiasis.

Modulation of DNA adduct formation by pre-existing adducts was examined in synthetic oligonucleotides and genomic DNA (calf thymus); genotoxins studied were N-acetoxy-acetylaminofluorene (N-AcO-AAF), aminofluorene (AF), aflatoxin B1-8,9-epoxide (AFB1-8,9-epoxide), and dimethylsulfate (DMS). Oligodeoxynucleotides containing either guanine-C8-AAF (Gua-C8-AAF) or Gua-C8-AF adducts and a neighboring unadducted guanine (G) (target G), located 1, 2, or 4 nucleotides from the adduct, were reacted, as single- (ss) or double-stranded (ds) substrates, with dimethylsulfate (DMS) or AFB1-8,9-epoxide. A modified Maxam-Gilbert technique showed that the presence of the AAF adduct lowered the extent to which AFB1-8,9-epoxide, but not DMS, reacted with target G. Binding of AFB1-8,9-epoxide to the target G was attenuated (> or =5-fold) when the target was located immediately adjacent to an AAF, but not AF, adduct in ds-DNA. Reaction with AFB1-8,9-epoxide increased when the target G was located 2 or 4 nucleotides from the AAF adduct. Pretreatment of calf thymus DNA with AAF (0-1.8% nucleotides modified) reduced levels of Gua-N7-AFB1 adducts formed after subsequent treatment with AFB1-8,9-epoxide. Pretreatment of calf thymus DNA with AFB1 did not alter levels of adducts formed after subsequent treatment with N-AcO-AAF. The supposition that aflatoxin B1-binding to DNA may be altered by conformational changes in the helix, due to the presence of a pre-existing AAF adduct, is supported by the absence of an effect by AF and confirmation of local denaturation of the oligomer helix by use of chemical probes hydroxylamine and diethylpyrocarbonate. Nonetheless, the importance of changes in the nucleophilicity of neighboring nucleotides and local steric effects cannot be ruled out.

Most animal genotoxicity studies have used exposures to single chemicals; humans, however, are potentially exposed to mixtures of genotoxins. Cancer and developmental toxicity risks associated with genotoxins in mixture are generally estimated by assuming additivity of the components. Two or more genotoxins acting sequentially or simultaneously may present a greater or lesser hazard than that predicted by simple addition of their potencies. Previously, we studied the effect of one genotoxin on the binding of a second genotoxin to DNA in an in vitro system and demonstrated that consecutive binding of the two toxins was not additive. In the present study, the effect of one genotoxin on the mutagenicity of another was evaluated for two well-known genotoxins using the Salmonella assay. Pretreatment of frameshift strains TA98 and TA1538 with AFB1-8,9-epoxide (17.3 ng/plate) enhanced the mutagenicity induced by subsequent exposure to N-acetoxy-acetylaminofluorene (N-AcO-AAF) approximately 2-3 times above theoretical values for additivity. Pretreatment of base-substitution strain TA100 with N-AcO-AAF (0.1 microg/plate) inhibited the mutagenicity following subsequent exposure to AFB1-8,9-epoxide by 3 times below the theoretical additive value. Concentration-response relationships for these enhancing or inhibitory effects were demonstrated using increasing concentrations of the first genotoxin during pretreatment. These results demonstrate effects, other than additive, of sequential exposures to two genotoxins on the induction of mutations in a bacterial system.

Acid protease inhibitor 1,2-epoxy-3-(p-nitrophenoxy)propane (ENPP) is commonly used in research as a substrate for glutathione-S-transferase activity (GST) and recently was found to inhibit human immunodeficiency virus 1 (HIV-1) protease. The question of DNA-adduct formation and mutagenicity was investigated and found that ENPP causes DNA damage and acts directly to induce mutagenicity in Salmonella. Using HPLC analysis, ENPP was shown to bind covalently to guanine residues. The Salmonella mutagenicity assay indicated that ENPP enhanced the mutation frequencies in the base-substitution strain TA00 by more than 20 times above the background. Its mutagenic potency was comparable to that of well-known carcinogens, N-methyl-N-nitrosourea (MNU) and aflatoxin B(1)-8,9-epoxide (AFB(1)-8,9-epoxide). The results suggest that ENPP should be classified as a mutagenic compound and a potential carcinogen., (Copyright 1999 Academic Press.)

The reactivity of guanines in an oligonucleotide containing mutational hot spots within the p53 gene (codons 248 and 249), 5'-CCG1G2AG3G4CCCA-3', toward dimethyl sulfate (DMS) and aflatoxin B1-8,9-epoxide (AFB1-8,9-epoxide) was investigated by a modified Maxam-Gilbert technique. 5-Methylcytosine in the CpG site of codon 248 did not appear to modulate the reactivity of target guanines G1, G2, G3, and G4 toward either genotoxin when compared to the sequence containing a nonmethylated CpG site. A similar experiment was conducted in which a 0.5-kb fragment of the human HPRT gene containing exon 1 and several CpG sites was treated with UV-activated aflatoxin B1. Results showed that guanine adduct formation was independent of the methylation status of the CpG site. These findings are discussed in relation to other studies that have shown that cytosine methylation has an inhibiting effect, an enhancing effect, or no effect on adduct formation with nearby guanine nucleotides., (Copyright 1999 Academic Press.)

Inbred mice vary in susceptibility to colon carcinogens such as 1,2-dimethylhydrazine (DMH). Differential susceptibility may depend, in part, on formation of promutagenic DNA methyl adducts within target colonic mucosa. The present study was undertaken to evaluate the extent of DNA adduct formation in susceptible (SWR) and resistant (AKR) mice acutely exposed to the colon carcinogen azoxymethane (AOM), a direct metabolite of DMH. In the first experiment, 8-week-old SWR and AKR mice were treated i.p. with 20 mg/kg AOM and sacrificed 6 h later. DNA was isolated from distal colon and liver, and O6-methylguanine (O6-MeGua) adduct levels were assessed by immunoslot blot (ISB) analysis, using a monospecific antibody raised against O6-methyldeoxyguanosine. HPLC-fluorescence detection was also used to quantitate 06-MeGua and 7-methylguanine (7-MeGua), and to generate standard curves. At 6 h, both O6-MeGua and 7-MeGua were significantly higher (2- to 3-fold, p < 0.05) in AKR colon, while an opposite pattern was found in liver. In Experiment 2, mice were injected with AOM (20 mg/kg) and euthanized 12 and 48 h later. At 12 h, O6-MeGua levels were higher in colons (1.4-fold) of SWR mice. Forty-eight hours after treatment, however, adduct levels in colon were markedly (5-fold) reduced in SWR but were unchanged from 12 h in AKR. To further compare activation of AOM in both strains, colon microsomes were incubated with AOM and calf thymus DNA. Comparable levels of O6-MeGua were detected by ISB, demonstrating equivalent metabolic capacity in both SWR and AKR mice. These studies suggest that differential susceptibility to AOM-induced colon carcinogenesis is not based on initial target tissue DNA alkylation and unlikely to depend on differential metabolic capacity.