Capsicum-derived ingredients function as skin-conditioning agents - miscellaneous, external analgesics, flavoring agents, or fragrance components in cosmetics. These ingredients are used in 19 cosmetic products at concentrations as high as 5%. Cosmetic-grade material may be extracted using hexane, ethanol, or vegetable oil and contain the full range of phytocompounds that are found in the Capsicum annuum or Capsicum frutescens plant (aka red chiles), including Capsaicin. Aflatoxin and N-nitroso compounds (N-nitrosodimethylamine and N-nitrosopyrrolidine) have been detected as contaminants. The ultraviolet (UV) absorption spectrum for Capsicum Annuum Fruit Extract indicates a small peak at approximately 275 nm, and a gradual increase in absorbance, beginning at approximately 400 nm. Capsicum and paprika are generally recognized as safe by the U.S. Food and Drug Administration for use in food. Hexane, chloroform, and ethyl acetate extracts of Capsicum Frutescens Fruit at 200 mg/kg resulted in death of all mice. In a short-term inhalation toxicity study using rats, no difference was found between vehicle control and a 7% Capsicum Oleoresin solution. In a 4-week feeding study, red chilli (Capsicum annuum) in the diet at concentrations up to 10% was relatively nontoxic in groups of male mice. In an 8-week feeding study using rats, intestinal exfoliation, cytoplasmic fatty vacuolation and centrilobular necrosis of hepatocytes, and aggregation of lymphocytes in the portal areas were seen at 10% Capsicum Frutescens Fruit, but not 2%. Rats fed 0.5 g/kg day- 1 crude Capsicum Fruit Extract for 60 days exhibited no significant gross pathology at necropsy, but slight hyperemia of the liver and reddening of the gastric mucosa were observed. Weanling rats fed basal diets supplemented with whole red pepper at concentrations up to 5.0% for up to 8 weeks had no pathology of the large intestines, livers, and kidneys, but destruction of the taste buds and keratinization and erosion of the gastrointestinal (GI) tract were noted in groups fed 0.5% to 5.0% red pepper. The results of 9-and 12-month extension of this study showed normal large intestines and kidneys. In rabbits fed Capsicum Annuum Powder at 5 mg/kg day- 1 in the diet daily for 12 months damage to the liver and spleen was noted. A rabbit skin irritation test of Capsicum Annuum Fruit Extract at concentrations ranging from 0.1% to 1.0% produced no irritation, but Capsicum Frutescens Fruit Extract induced concentration-dependent (at 25 to 500 mug/ml) cytotoxicity in a human buccal mucosa fibroblast cell line. An ethanol extract of red chili was mutagenic in Salmonella typhimurium TA98, but not in TA100, or in Escherichia coli. Other genotoxicity assays gave a similar pattern of mixed results. Adenocarcinoma of the abdomen was observed in 7/20 mice fed 100 mg red chilies per day for 12 months; no tumors were seen in control animals. Neoplastic changes in the liver and intestinal tumors were observed in rats fed red chili powder at 80 mg/kg day- 1 for 30 days, intestinal and colon tumors were seen in rats fed red chili powder and 1,2-dimethyl hydrazine, but no tumors were observed in controls. In another study in rats, however, red chile pepper in the diet at the same dose decreased the number of tumors seen with 1,2-dimethylhydrazine. Other feeding studies evaluated the effect of red chili peppers on the incidence of stomach tumors produced by N-methyl-N'-nitro-N-nitrosoguanidine, finding that red pepper had a promoting effect. Capsicum Frutescens Fruit Extract promoted the carcinogenic effect of methyl(acetoxymethyl)nitrosamine (carcinogen) or benzene hexachloride (hepatocarcinogen) in inbred male and female Balb/c mice dosed orally (tongue application). Clinical findings include symptoms of cough, sneezing, and runny nose in chili factory workers. Human respiratory responses to Capsicum Oleoresin spray include burning of the throat, wheezing, dry cough, shortness of breath, gagging, gasping, inability to breathe or speak, and, rarely, cyanosis, apnea, and respiratory arrest. A trade name mixture containing 1% to 5% Capsicum Frutescens Fruit Extract induced very slight erythema in 1 of 10 volunteers patch tested for 48 h. Capsicum Frutescens Fruit Extract at 0.025% in a repeated-insult patch test using 103 subjects resulted in no clinically meaningful irritation or allergic contact dermatitis. One epidemiological study indicated that chili pepper consumption may be a strong risk factor for gastric cancer in populations with high intakes of chili pepper; however, other studies did not find this association. Capsaicin functions as an external analgesic, a fragrance ingredient, and as a skin-conditioning agent - miscellaneous in cosmetic products, but is not in current use. Capsaicin is not generally recognized as safe and effective by the U.S. Food and Drug Administration for fever blister and cold sore treatment, but is considered to be safe and effective as an external analgesic counterirritant. Ingested Capsaicin is rapidly absorbed from the stomach and small intestine in animal studies. Subcutaneous injection of Capsaicin in rats resulted in a rise in the blood concentration, reaching a maximum at 5 h; the highest tissue concentrations were in the kidney and lowest in the liver. In vitro percutaneous absorption of Capsaicin has been demonstrated in human, rat, mouse, rabbit, and pig skin. Enhancement of the skin permeation of naproxen (nonsteroidal anti-inflammatory agent) in the presence of Capsaicin has also been demonstrated. Pharmacological and physiological studies demonstrated that Capsaicin, which contains a vanillyl moiety, produces its sensory effects by activating a Ca2 +-permeable ion channel on sensory neurons. Capsaicin is a known activator of vanilloid receptor 1. Capsaicin-induced stimulation of prostaglandin biosynthesis has been shown using bull seminal vesicles and rheumatoid arthritis synoviocytes. Capsaicin inhibits protein synthesis in Vero kidney cells and human neuroblastoma SHSY-5Y cells in vitro, and inhibits growth of E. coli, Pseudomonas solanacearum, and Bacillus subtilis bacterial cultures, but not Saccharomyces cerevisiae. Oral LD50 values as low as 161.2 mg/kg (rats) and 118.8 mg/kg (mice) have been reported for Capsaicin in acute oral toxicity studies, with hemorrhage of the gastric fundus observed in some of the animals that died. Intravenous, intraperitoneal, and subcutaneous LD50 values were lower. In subchronic oral toxicity studies using mice, Capsaicin produced statistically significant differences in the growth rate and liver/body weight increases. Capsaicin is an ocular irritant in mice, rats, and rabbits. Dose-related edema was observed in animals receiving Capsaicin injections into the hindpaw (rats) or application to the ear (mice). In guinea pigs, dinitrochlorobenzene contact dermatitis was enhanced in the presence of Capsaicin, injected subcutaneously, whereas dermal application inhibited sensitization in mice. Immune system effects have been observed in neonatal rats injected subcutaneously with Capsaicin. Capsaicin produced mixed results in S. typhimurium micronucleus and sister-chromatid exchange genotoxicity assays. Positive results for Capsaicin were reported in DNA damage assays. Carcinogenic, cocarcinogenic, anticarcinogenic, antitumorigenic, tumor promotion, and anti-tumor promotion effects of Capsaicin have been reported in animal studies. Except for a significant reduction in crown-rump length in day 18 rats injected subcutaneously with Capsaicin (50 mg/kg) on gestation days 14, 16, 18, or 20, no reproductive or developmental toxicity was noted. In pregnant mice dosed subcutaneously with Capsaicin, depletion of substance P in the spinal cord and peripheral nerves of pregnant females and fetuses was noted. In clinical tests, nerve degeneration of intracutaneous nerve fibers and a decrease in pain sensation induced by heat and mechanical stimuli were evident in subjects injected intradermally with Capsaicin. An increase in mean inspiratory flow was reported for eight normal subjects who inhaled nebulized 10- 7 M Capsaicin. The results of provocative and predictive tests involving human subjects indicated that Capsaicin is a skin irritant. Overall, studies suggested that these ingredients can be irritating at low concentrations. Although the genotoxicity, carcinogenicity, and tumor promotion potential of Capsaicin have been demonstrated, so have opposite effects. Skin irritation and other tumor-promoting effects of Capsaicin appear to be mediated through interaction with the same vanilloid receptor. Given this mechanism of action and the observation that many tumor promoters are irritating to the skin, the Panel considered it likely that a potent tumor promoter may also be a moderate to severe skin irritant. Thus, a limitation on Capsaicin content that would significantly reduce its skin irritation potential is expected to, in effect, lessen any concerns relating to tumor promotion potential. Because Capsaicin enhanced the penetration of an anti-inflammatory agent through human skin, the Panel recommends that care should be exercised in using ingredients that contain Capsaicin in cosmetic products. The Panel advised industry that the total polychlorinated biphenyl (PCB)/pesticide contamination should be limited to not more than 40 ppm, with not more than 10 ppm for any specific residue, and agreed on the following limitations for other impurities: arsenic (3 mg/kg max), heavy metals (0.002% max), and lead (5 mg/kg max). Industry was also advised that aflatoxin should not be present in these ingredients (the Panel adopted </=15 ppb as corresponding to "negative" aflatoxin content), and that ingredients derived from Capsicum annuum and Capsicum Frutescens Plant species should not be used in products where N-nitroso compounds may be formed.(ABSTRACT TRUNCATED)

Octoxynols are ethoxylated alkylphenols in which the size of the molecule is related to the number of moles of ethylene oxide used in synthesis. Reactions are performed at elevated temperature, under pressure, and in the presence of NaOH. It is possible that the synthesis may leave trace amounts of ethylene oxide, 1,4-dioxane, and unreacted C9 phenols. Octoxynols of various chain lengths as well as octoxynol salts and organic acids function in cosmetics either as surfactants--emulsifying agents, surfactants--cleansing agents, surfactant--solubilizing agents, or surfactants--hydrotropes in a wide variety of cosmetic products at concentrations ranging from 0.0008% to 25%, with most less than 5.0%. The octoxynols are chemically similar to nonoxynols, the safety of which were previously considered. Long-chain nonoxynols (9 and above) were considered safe as used, whereas short-chain nonoxynols (8 and below) were considered safe as used in rinse-off products and safe at concentrations less than 5% in leave-on formulations. Acute exposure of hamsters to Octoxynol-9 by bronchopulmonary lavage produced pneumonia, pulmonary edema, and intra-alveolar hemorrhage. Octoxynol-9 at doses over 1 g/kg was toxic in rats and in mice in acute oral toxicity studies. No significant effects were noted in short-term oral studies of Octoxynol-9 in rats, in subchronic oral studies of Octoxynol-40 in rats and dogs, or in chronic oral studies of Octoxynol-40 in rats. The intraperitoneal LD50 of Octoxynol-9 in rats and mice was around 100 mg/kg. In skin irritation studies, octoxynols ranged from nonirritating to moderately irritating. Octoxynols were not ocular irritants in one rabbit study, but in others there was ocular irritation. No immune system toxicity in CF-1 female mice was noted following the intraperitoneal injection of Octoxynol-9 followed by subcutaneous immunization with sheep red blood cells (SRBCs). Octoxynol-9 produced no humoral and cell-mediated immune responses, or autoimmune response in mice. In the Ames test, Octoxynol-1 was not mutagenic with and without metabolic activation nor was Octoxynol-9 clastogenic. Results for Octoxynol-9 were negative in the following assays: unscheduled DNA synthesis, hypoxanthine guanine phosphoribosyl transferase mutation assay, malignant transformation assay, DNA alkaline unwinding test, and mouse lymphoma thymidine kinase locus forward mutation assay. Ethoxylated alkylphenols are generally considered to be estrogenic in that they mimic the effects of estradiol. Dermal exposure at three dose levels of rats to Octoxynol-9 failed to induce any malformations by category (external, visceral, or skeletal) or by individual anatomical location that were different from controls at statistically significant level. An increased incidence of a vestigial thoracic rib was observed in all dose groups. Octoxynol-9 also did not induce developmental toxicity (number of viable litters, liveborn per litter, percentage survival, birth weight per pup, and weight gain per pup) in female specific pathogen-free CD-1 mice dosed daily by gavage on gestation days 6 through 13. No reproductive toxicity was seen in male albino rats which received 5% Octoxynol-40 in the diet daily for 3 months; however, in an in vitro test, Octoxynol-9 (0.24 mg/ml) totally immobilized all human spermatozoa within 20 s. Women who used Nonoxynol-9 or Octoxynol-9 as spermicides, but who did become pregnant, did not have an increase in the overall risk of fetal malformations. In a human skin irritation study, formulations containing 2.0% Octoxynol-9 were classified as moderately irritating and minimally irritating, respectively, in a 24-h single-insult, occlusive patch test. Octoxynol-9 (1.0%) was classified as a nonirritant in a clinical study of nine subjects patch tested for 4 consecutive days. The skin sensitization potential of Octoxynols-1,-3,-5,-9, and -13 was evaluated using 50 subjects. Octoxynol-1 induced sensitization in two subjects; all other results were negative. No sensitization was observed in the following studies: 8.0% Octoxynol-9 in 103 subjects, 0.5% Octoxynol-9 in 102 subjects, and 0.1% Octoxynol-9 in 206 subjects. Concerns about even trace levels of 1,4-dioxane, ethylene oxide, or unreacted C9 led to the recommendation that levels be limited. Concerns about the ocular irritancy of short-chain octoxynols led to a recommendation that they should not be used in products that will be used in the area surrounding the eyes. A limitation on the use concentration for short-chain octoxynols (8 and below) arose from consideration of the skin sensitization potential of octoxynols and the recognition that the short-chain octoxynols could be absorbed into the skin more than the long-chain octoxynols. Overall, based on the available data, it was concluded that long-chain octoxynols (9 and above) are safe as used, whereas short-chain octoxynols (8 and below) are safe as used in rinse-off products and safe at concentrations less than 5% in leave-on formulations.

MIBK (Methyl Isobutyl Ketone) is an aliphatic ketone that functions as both a denaturant and solvent in cosmetic products. Current use in cosmetic products is very limited, but MIBK is reported to be used in one nail correction pen (volume = 3 ml) at a concentration of 21%. The maximum percutaneous absorption rate in guinea pigs is 1.1 micromol/min/cm2 at 10 to 45 min. Metabolites include 4-hydroxy-4-methyl-2-pentanone (oxidation product) and 4-methyl-2-pentanol (4-MPOL)(reduction product). Values for the serum half-life and total clearance time of MIBK in animals were 66 min and 6 h, respectively. In clinical tests, most of the absorbed MIBK had been eliminated from the body 90 min post exposure. MIBK was not toxic via the oral or dermal route of exposure in acute, short-term, or subchronic animal studies, except that nephrotoxicity was observed in rats dosed with 1 g/kg in a short-term study. MIBK was an ocular and skin irritant in animal tests. Ocular irritation was noted in 12 volunteers exposed to 200 ppm MIBK for 15 min in a clinical test. A depression of the vestibulo-oculomotor reflex was seen with intravenous infusion of MIBK (in an emulsion) at 30 microM/kg/min in female rats. The no-observed-effect level in rats exposed orally to MIBK was 50 mg/kg. Both gross and microscopic evidence of lung damage were reported in acute inhalation toxicity studies in animals. Short-term and subchronic inhalation exposures (as low as 100 ppm) produced effects in the kidney and liver that were species and sex dependent. Dermal doses of 300 or 600 mg/kg for 4 months in rats produced reduced mitotic activity in hair follicles, increased thickness of horny and granular cell layers of the epidermis, a decrease in the number of reactive centers in follicles (spleen), an increase in the number of iron-containing pigments in the area of the red pulp (spleen), and a reduction in the lipid content of the cortical layer of the adrenal glands. Neuropathological changes in the most distal portions of the tibial and ulnar nerves were observed in young adult rats which inhaled 1500 ppm MIBK for up to 5 months. No adverse effects were seen in any other neurological end point by any route of exposure in other studies using rats or other animal species. Clinical tests demonstrated a threshold for MIBK-induced irritation of the lungs at 0.03 to 0.1 mg/L after 1 min of respiration. MIBK was not mutagenic in the Ames test or in a mitotic gene-conversion assay in bacteria. Mammalian mutagenicity test results were also negative in the following assays: mouse lymphoma, unscheduled DNA synthesis, micronucleus, cell transformation, and chromosome damage. MIBK did not induce any treatment-related increases in embryotoxicity or fetal malformations in pregnant Fischer 344 rats or CD-1 mice that inhaled MIBK at concentrations of 300, 1000, or 3000 ppm. There was evidence of treatment-related maternal toxicity only at the highest concentration tested. MIBK applied to the tail of rats daily at doses of 300 or 600 mg/kg for 4 months produced changes in the testes, including a reduction in the number of spermatocytes, spermatids, and spermatozoa. An ongoing carcinogenicity study of MIBK being conducted by the National Toxicology Program will be considered when the results are available. On the basis of the information that is currently available, MIBK is considered safe as used in nail polish removers and as an alcohol denaturant in cosmetic products.

Acetyl Triethyl Citrate, Acetyl Tributyl Citrate, Acetyl Trihexyl Citrate, and Acetyl Trioctyl Citrate all function as plasticizers in cosmetics. Additionally, the Trihexyl and Trioctyl forms are described as skin-conditioning agents-emollients, although there are currently no reported uses of Acetyl Trihexyl Citrate or Acetyl Trioctyl Citrate. Acetyl Triethyl Citrate and Acetyl Tributyl Citrate are used in nail products at concentrations up to 7%. Recognizing that there are no reported uses of Acetyl Trihexyl or Trioctyl Citrate, if they were to be used in the future, their concentration of use is expected to be no higher than that reported for Acetyl Triethyl and Tributyl Citrate. These ingredients were sufficiently similar in structure that safety test data on one were considered applicable to all. Approximately 99% of orally administered Acetyl Tributyl Citrate is excreted-intermediate metabolites include acetyl citrate, monobutyl citrate, acetyl monobutyl citrate, dibutyl citrate, and acetyl dibutyl citrate. In acute, short-term, subchronic, and chronic feeding studies, these ingredients were relatively nontoxic. Differences from controls were either not statistically significant or not related to any organ toxicity. Ocular exposures produced moderate reactions that cleared by 48 hours after instillation. Dermal application was not toxic in rabbits. In a guinea pig maximization test, Acetyl Triethyl Citrate was a sensitizer whereas Acetyl Tributyl Citrate was not. Limited clinical testing of Acetyl Triethyl Citrate and Acetyl Tributyl Citrate was negative for both skin irritation and sensitization. These clinical data were considered more relevant than the guinea pig maximization data, suggesting to the Cosmetic Ingredient Review Expert Panel that none of these ingredients would be a sensitizer. Physiologic effects noted with intravenous delivery of Acetyl Triethyl Citrate or Acetyl Tributyl Citrate include dose-related decreases in blood pressure and intestinal muscular spasms. These ingredients were not genotoxic in bacterial or mammalian test systems. No significant differences in tumor induction (lymphomas) were noted in rats fed Acetyl Tributyl Citrate for 2 year. Acetyl Tributyl Citrate was not a developmental or reproductive toxicant in studies in mice and rats. Based on all the available data, these ingredients were considered safe as used in cosmetics.

Ethoxyethanol is an ether alcohol described as a solvent and viscosity-decreasing agent for use in cosmetics. Ethoxyethanol Acetate is the ester of Ethoxyethanol and acetic acid described as a solvent for use in cosmetics. Although these ingredients have been used in the past, neither ingredient is in current use. Ethoxyethanol is produced by reacting ethylene oxide with ethyl alcohol. Ethoxyethanol Acetate is produced via an esterification of Ethoxyethanol and acetic acid, acetic acid anhydride, or acetic chloride. Ethoxyethanol is metabolized to ethoxyacetaldehyde, which is further metabolized to ethoxyacetic acid, which is also a metabolite of Ethoxyethanol Acetate. Low to moderate acute inhalation toxicity is seen in animals studies. Acute oral toxicity studies in several species reported kidney damage, including extreme tubular degeneration. Kidney damage was also seen in acute dermal toxicity studies in rats and rabbits. Minor liver and kidney damage was also seen in short-term studies of rats injected subcutaneously with Ethoxyethanol, but was absent in dogs dosed intravenously. Mixed toxicity results were also seen in subchronic tests in mice and rats. Ethoxyethanol and Ethoxyethanol Acetate were mild to moderate eye irritants in rabbits; mild skin irritants in rabbits, and nonsensitizing in guinea pigs. Most genotoxicity tests were negative, but chromosome aberrations and sister-chromatid exchanges were among the positive results seen. Numerous reproductive and developmental toxicity studies, across several species, involving various routes of administration, indicate that Ethoxyethanol and Ethoxyethanol Acetate are reproductive toxicants and teratogens. Mild anemia was reported in individuals exposed occupationally to Ethoxyethanol, which resolved when the chemical was not used. Reproductive effects have been noted in males exposed occupationally to Ethoxyethanol. Although there are insufficient data to determine the potential carcinogenic effects of Ethoxyethanol or Ethoxyethanol Acetate, there is evidence that these chemicals are absorbed across human skin and that they are reproductive and developmental toxicants via dermal exposure. Therefore, these ingredients are unsafe for use in cosmetic formulations.