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.
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.
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.
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.
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
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.
Azulene is an extract from the volatile oil of several perennial herbs and is detected in tobacco smoke. It functions as a skin conditioning agent in cosmetic formulations, including hair dyes. Azulene is reported to be used in a wide range of cosmetic formulations, but these reported uses are likely to be uses of guaiazulene, a chemically related colorant, because there are currently no suppliers of Azulene to the cosmetics industry. The anti-inflammatory action of Azulene has been demonstrated in several animal studies. Effects at the cellular level are reported to include inhibition of respiration and growth, but no effect on ciliary activity or membrane permeability. Relatively low oral toxicity was seen in acute animal studies. Azulene was not mutagenic in an Ames test, with and without metabolic acfivation. An allergic response to Azulene was noted in one case report. These data were clearly insufficient to support the safety of Azulene in cosmetics. Additional data needed to make a safety assessment include: methods of manufacture and impurities, especially naphthalenes; current concentration of use; skin penetration, if there is significant skin penetration, then both a 28-day dermal toxicity study to assess general skin and systemic toxicity and a reproductive and developmental toxicity study are needed; one genotoxicity study in a mammalian system, if positive, then a 2-year dermal carcinogenesis study using National Toxicology Program methods is needed; skin irritation and sensitization in animals or humans; and ocular toxicity.
Ascorbyl Palmitate, Ascorbyl Dipalmitate, Ascorbyl Stearate, Erythorbic Acid, and Sodium Erythorbate are related ingredients that function as antioxidants in cosmetic formulations. Ascorbyl Palmitate, Ascorbyl Dipalmitate, and Ascorbyl Stearate are esters and diesters of ascorbic acid with long-chain fatty acids. Erythorbic Acid is a stereoisomer of ascorbic acid and Sodium Erythorbate is the sodium salt of Erythorbic Acid. Although all of these ingredients are used, uses of Ascorbyl Palmitate and Erythorbic Acid predominate, with combined uses in over a thousand cosmetic formulations at low concentrations. Ascorbyl Palmitate is used at concentrations between 0.01 and 0.2% , and Erythorbic Acid is used at concentrations of 0.5-1% . Ascorbyl Palmitate has vitamin C activity approximately equal to that of L-ascorbic acid, whereas Erythorbic Acid has only 5% activity. The esters are likely to penetrate the skin readily, but the acid and its salt are not likely to penetrate. These ingredients exhibit low acute oral toxicity in animals. In chronic feeding studies, decreased body weight gain, the formation of oxalate stones in the bladder, and hyperplasia were seen in rats fed high levels of Ascorbyl Palmitate. Ascorbyl Palmitate (10%) and Ascorbyl Dipalmitate (100%) were not irritating to the intact skin of albino rabbits. Ascorbic Acid (30 % ) itself caused barely perceptible erythema and Sodium Erythorbate powder caused no irritation to the intact and abraded skin of rabbits. In animal studies, Ascorbic acid was not a sensitizer, and Erythorbic Acid (10%) applied topically to porcine skin reduced ultraviolet B (UVB)-induced phototoxicity. In clinical studies, Ascorbyl Palmitate caused no dermal irritation or sensitization. These ingredients are minimally irritating to the eye. Sodium Erythorbate did not cause fetal or maternal toxicity or developmental toxicity in rats and mice fed high levels. Although these ingredients were generally negative in a wide range of genotoxicity tests, Erythorbic Acid and Sodium Erythorbate did produce isolated positive genotoxicity test results. As antioxidants, these ingredients have been studied in animals after initiation with various carcinogens. In some cases reductions in tumor incidence were seen, in others no effect was noted. In no case did treatment with these ingredients increase tumor incidence. The highest use concentrations of Erythorbic Acid and Sodium Erythorbate are in oxidative hair dyes, where they are completely consumed in the chemical reaction that takes place at mixing. The fatty acid esters of ascorbic acid are used at lower concentrations in leave-on formulations. In consideration of these uses and based on the available safety test data, Ascorbyl Palmitate, Ascorbyl Dipalmitate, Ascorbyl Stearate, Erythorbic Acid, and Sodium Erythorbate are safe for use as cosmetic ingredients in the present practices of use.
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