F. Alan Andersen

Annual Review of Cosmetic Ingredient Safety Assessments: 2007-2010.

This Annual Review of Cosmetic Ingredient Safety Assessments updates and affirms the findings of the Cosmetic Ingredient Review (CIR) Expert Panel’s assessment of almost 30 compounds used in cosmetic ingredients. The review also summarizes new findings from epidemiology studies of hair dyes. The CIR Expert Panel’s re-review process is intended to uncover any new data since the last safety assessment. In some cases, newly available data are largely redundant compared with the data available in the original safety assessment. In other cases, new data present new safety issues. If after considering the newly available information, the CIR Expert Panel decides to not reopen a safety assessment, this finding, along with any background material, is summarized and announced publicly. To assure that the scientific community is aware of any new information and the decision not to reopen, this Annual Review of Cosmetic Ingredient Safety Assessments is prepared. A list of reference sources is provided after each ingredient re-review summary that updates the available published literature and includes any unpublished data made available since the original safety assessment. The re-review also captures information on the industry’s current practices of ingredient use, updating the data available in the earlier report. Although this material provides the opinion of the CIR Expert Panel regarding the new data described, it does not constitute a full safety review. The CIR Expert Panel has assessed the safety of over 2100 cosmetic ingredients since its inception in 1976. These safety assessments were published in the Journal of Environmental Pathology and Toxicology in 1980, the Journal of the American College of Toxicology, from 1982 to 1996, and since then in the International Journal of Toxicology. The ingredients the CIR Expert Panel reconsidered during the 2007-2010 period and did not reopen are: Acetamide MEA 5-Bromo-5-nitro-1,3-dioxane Butyl benzyl phthalate t-Butyl hydroquinone (TBHQ) Chlorhexidine, chlorhexidine dihydrochloride, chlorhexidine digluconate, chlorhexidine diacetate 2-Chloro-p-phenylenediamine and 2-chloro-p-phenylenediamine sulfate 2,4-Diaminophenol and 2,4-diaminophenol dihydrochloride Diisopropylamine Disperse blue 1 Disperse violet 1 Ethyl hexanediol HC Blue No. 2 HC Red No. 3 HC Yellow No. 2 Hydroxybenzomorpholine Isopropyl isostearate Lauramine oxide and stearamine oxide Methenamine 1-Naphthol Phenoxyethanol Phenyl methyl pyrazolone N-Phenyl-p-phenylenediamine Polyoxymethylene urea Polyquaternium-7 Quaternium-22 Shellac Sodium and potassium bromate Stearpyrium chloride and lapyrium chloride

Final Report of the Safety Assessment of Methylisothiazolinone

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.

Final Report of the Safety Assessment of Kojic Acid as Used in Cosmetics

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.

Amended Final Report On the Safety Assessment of Dioctyl Sodium Sulfosuccinate

Dioctyl Sodium Sulfosuccinate is an anionic surfactant used in a wide variety of cosmetic formulations. In September 1994, the Cosmetic Ingredient Review (CIR) Expert Panel evaluated the ingredient to be safe up to 0.42% in cosmetic formulations. Since that time, CIR received a petition to re-open the safety assessment based on new clinical data. This amendment is a compilation of data contained in the original plus the data received in the petition; the latter appear at the end of this document. Studies conducted in the 1940s indicate that the oral LD50 in rats can be as low as 1.9 g/kg. Short-term subchronic and chronic animal studies of the same vintage found little toxicity at levels around 1% of the LD50 level. Inhalation studies likewise had few findings. Dioctyl Sodium Sulfosuccinate was minimally irritating to intact animal skin, but moderate to severely irritating to abraded skin. A concentration of 25% was a severe ocular irritant, but 10% produced little or no irritation. Mutagenesis tests were negative. A repeated insult patch test (RIPT) in 110 individuals produced no sensitization at a concentration of 5%. Erythema was noted during induction in a number of subjects at concentrations ≤5%. The CIR Expert Panel recognized that surfactants such as Dioctyl Sodium Sulfosuccinate would likely produce irritation under the conditions of a RIPT. The Panel cautioned that as the ingredient is a cumulative irritant, care should be taken to avoid irritancy in formulations intended for prolonged contact with the skin. The Panel concluded that Dioctyl Sodium Sulfosuccinate is safe for use in cosmetics.

Final Report on the Safety Assessment of Bisabolol

Bisabolol is a naturally occuring unsaturated monocyclic terpene alcohol, the alpha form of which is used in a wide range of cosmetic formulations as a skin conditioning agent at low concentrations ranging from 0.001% in lipstick to 1% in underarm deodorants. Animal studies demonstrate that Bisabolol is well absorbed following dermal exposure and one study using cadaver skin demonstrated that Bisabolol can enhance the penetration of 5-fluorouracil. Bisabolol was relatively nontoxic in acute oral studies in rats, dogs, and monkeys. Short-term oral exposure using rats did produce inflammatory changes in several organs, and reduced body weight and increased liver weights relative to body weight in dogs. The no-observable-adverse-effect level in a 28-day dermal toxicity study using rats was 200 mdkg/day. No evidence of sensitization or photosensitization was found. Bisabolol was negative in bacterial and mammalian genotoxicity tests, and it did not produce reproductive or developmental toxicity in rats. The results of oral and dermal toxicity, genotoxicity, reproductive/developmental toxicity, sensitization, and photosensitization studies show little toxicity at levels expected in cosmetic formulafions. Formulators should be alert to the possibility that use of Bisabolol may increase the penetration of other components of a cosmetic formulation. Based on the available data it was concluded that Bisabolol is safe as used in cosmetic formulafions.

Final Report of the Amended Safety Assessment of Sodium Laureth Sulfate and Related Salts of Sulfated Ethoxylated Alcohols

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.

Final Amended Safety Assessment of Hydroquinone as Used in Cosmetics

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.

Final Report of the Cosmetic Ingredient Review Expert Panel Amended Safety Assessment of Calendula officinalis–Derived Cosmetic Ingredients

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.

Safety Assessment of Cyclomethicone, Cyclotetrasiloxane, Cyclopentasiloxane, Cyclohexasiloxane, and Cycloheptasiloxane

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.

Safety Assessment of Propylene Glycol, Tripropylene Glycol, and PPGs as Used in Cosmetics:

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.