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Query: UMLS:C0011570 (depression)
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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.
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PMID:Safety assessment of MIBK (methyl isobutyl ketone). 1516 37

Potassium Silicate, Sodium Metasilicate, and Sodium Silicate combine metal cations with silica to form inorganic salts used as corrosion inhibitors in cosmetics. Sodium Metasilicate also functions as a chelating agent and Sodium Silicate as a buffering and pH adjuster. Sodium Metasilicate is currently used in 168 formulations at concentrations ranging from 13% to 18%. Sodium Silicate is currently used in 24 formulations at concentrations ranging from 0.3% to 55%. Potassium Silicate and Sodium Silicate have been reported as being used in industrial cleaners and detergents. Sodium Metasilicate is a GRAS (generally regarded as safe) food ingredient. Aqueous solutions of Sodium Silicate species are a part of a chemical continuum of silicates based on an equilibrium of alkali, water, and silica. pH determines the solubility of silica and, together with concentration, determines the degree of polymerization. Sodium Silicate administered orally is readily absorbed from the alimentary canal and excreted in the urine. The toxicity of these silicates has been related to the molar ratio of SiO2/Na2O and the concentration being used. The Sodium Metasilicate acute oral LD50 ranged from 847 mg/kg in male rats to 1349.3 mg/kg in female rats and from 770 mg/kg in female mice to 820 mg/kg in male mice. Gross lesions of variable severity were found in the oral cavity, pharynx, esophagus, stomach, larynx, lungs, and kidneys of dogs receiving 0.25 g/kg or more of a commercial detergent containing Sodium Metasilicate; similar lesions were also seen in pigs administered the same detergent and dose. Male rats orally administered 464 mg/kg of a 20% solution containing either 2.0 or 2.4 to 1.0 ratio of sodium oxide showed no signs of toxicity, whereas doses of 1000 and 2150 mg/kg produced gasping, dypsnea, and acute depression. Dogs fed 2.4 g/kg/day of Sodium Silicate for 4 weeks had gross renal lesions but no impairment of renal function. Dermal irritation of Potassium Silicate, Sodium Metasilicate, and Sodium Silicate ranged from negligible to severe, depending on the species tested and the molar ratio and concentration tested. Sodium Metasilicate was negative in the local lymph node assay (LLNA), but a delayed-type hypersensitivity response was observed in mice. Potassium Silicate was nonirritating in two acute eye irritation studies in rabbits. Sodium Metasilicate (42.4% H2O) was corrosive to the rabbit eye. Sodium Silicate was a severe eye irritant in some eye irritation studies, but was irritating or nonirritating in others. A skin freshener containing Sodium Silicate was nonirritating. Sodium Metasilicate was nonmutagenic in bacterial cells. Rats given Sodium Silicate (600 and 1200 ppm of added silica) in the drinking water in reproductive studies produced a reduced number of offspring: to 67% of controls at 600 ppm and to 80% of controls at 1200 ppm. Three adult rats injected intratesticularly and subcutaneously with 0.8 mM/kg of Sodium Silicate showed no morphological changes in the testes and no effect on the residual spermatozoa in the ductus deferens. Sodium Metasilicate (37% in a detergent) mixed with water was a severe skin irritant when tested on intact and abraded human skin, but 6%, 7%, and 13% Sodium Silicate were negligible skin irritants to intact and abraded human skin. Sodium Silicate (10% of a 40% aqueous solution) was negative in a repeat-insult predictive patch test in humans. The same aqueous solution of Sodium Silicate was considered a mild irritant under normal use conditions in a study of cumulative irritant properties. The Cosmetic Ingredient Review (CIR) Expert Panel recognized the irritation potential of these ingredients, especially in leave-on products. However, because these ingredients have limited dermal absorption and Sodium Metasilicate is a GRAS direct food substance, the Panel deemed the ingredients safe for use in cosmetic products in the practices of use and concentration described in this safety assessment, when formulated to avoid irritation.
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PMID:Final report on the safety assessment of potassium silicate, sodium metasilicate, and sodium silicate. 1598 34

Glycyrrhetinic Acid and its salts and esters and Glycyrrhizic Acid and its salts and esters are cosmetic ingredients that function as flavoring agents or skin-conditioning agents - miscellaneous or both. These chemicals may be isolated from licorice plants. Glycyrrhetinc Acid is described as at least 98% pure, with 0.6% 24-OH-Glycyrrhetinic Acid, not more than 20 mu g/g of heavy metals and not more than 2 mu g/g of arsenic. Ammonium Glycyrrhizate has been found to be at least 98% pure and Dipotassium Glycyrrhizate has been found to be at least 95% pure. Glycyrrhetinic Acid is used in cosmetics at concentrations of up to 2%; Stearyl Glycyrrhetinate, up to 1%; Glycyrrhizic Acid, up to 0.1%; Ammonium Glycyrrhizate, up to 5%; Dipotassium Glycyrrhizate, up to 1%; and Potassium Glycyrretinate, up to 1%. Although Glycyrrhizic Acid is poorly absorbed by the intestinal tract, it may be hydrolyzed to Glycyrrhetinic Acid by a beta -glucuronidase produced by intestinal bacteria. Glycyrrhetinic Acid and Glycyrrhizic Acid bind to rat and human albumin, but do not absorb well into tissues. Glycyrrhetinic Acid and Glycyrrhizic Acid and metabolites are mostly excreted in the bile, with very little excreted in urine. Dipotassium Glycyrrhizate was undetectable in the receptor chamber when tested for transepidermal permeation through pig skin. Glycyrrhizic Acid increased the dermal penetration of diclofenac sodium in rat skin. Dipotassium Glycyrrhizate increased the intestinal absorption of calcitonin in rats. In humans, Glycyrrhetinic Acid potentiated the effects of hydrocortisone in the skin. Moderate chronic or high acute exposure to Glycyrrhizic Acid, Ammonium Glycyrrhizate, and their metabolites have been demonstrated to cause transient systemic alterations, including increased potassium excretion, sodium and water retention, body weight gain, alkalosis, suppression of the renin-angiotensis-aldosterone system, hypertension, and muscular paralysis; possibly through inhibition of 11beta -hydroxysteroid dehydrogenase-2 (11beta -OHSD2) in the kidney. Glycyrrhetinic Acid and its derivatives block gap junction intracellular communication in a dose-dependent manner in animal and human cells, including epithelial cells, fibroblasts, osteoblasts, hepatocytes, and astrocytes; at high concentrations, it is cytotoxic. Glycyrrhetinic Acid and Glycyrrhizic Acid protect liver tissue from carbon tetrachloride. Glycyrrhizic Acid has been used to treat chronic hepatitis, inhibiting the penetration of the hepatitis A virus into hepatocytes. Glycyrrhetinic Acid and Glycyrrhizic Acid have anti-inflammatory effects in rats and mice. The acute intraperitoneal LD(50) for Glycyrrhetinic Acid in mice was 308 mg/kg and the oral LD(50) was > 610 mg/kg. The oral LD(50) in rats was reported to be 610 mg/kg. Higher LD(50) values were generally reported for salts. Little short-term, subchronic, or chronic toxicity was seen in rats given ammonium, dipotassium, or disodium salts of Glycyrrhizic Acid. Glycyrrhetinic Acid was not irritating to shaved rabbit skin, but was considered slightly irritating in an in vitro test. Glycyrrhetinic Acid inhibited the mutagenic activity of benzo[a]pyrene and inhibited tumor initiation and promotion by other agents in mice. Glycyrrhizic Acid inhibited tumor initiation by another agent, but did not prevent tumor promotion in mice. Glycyrrhizic Acid delayed mortality in mice injected with Erlich ascites tumor cells, but did not reduce the mortality rate. Ammonium Glycyrrhizate was not genotoxic in in vivo and in vitro cytogenetics assays, the dominant lethal assay, an Ames assay, and heritable translocation tests, except for possible increase in dominant lethal mutations in rats given 2000 mg/kg day(-1) in their diet. Disodium Glycyrrhizate was not carcinogenic in mice in a drinking water study at exposure levels up to 12.2 mg/kg day(-1) for 96 weeks. Glycyrrhizate salts produced no reproductive or developmental toxicity in rats, mice, golden hamsters, or Dutch-belted rabbits, except for a dose-dependent increase (at 238.8 and 679.9 mg/kg day(-1)) in sternebral variants in a study using rats. Sedation, hypnosis, hypothermia, and respiratory depression were seen in mice given 1250 mg/kg Glycyrrhetinic Acid intraperitoneally. Rats fed a powdered diet containing up to 4% Ammonium Glycyrrhizate had no treatment related effects in motor function tests, but active avoidance was facilitated at 4%, unaffected at 3%, and depressed at 2%. In a study of 39 healthy volunteers, a no effect level of 2 mg/kg/day was determined for Glycyrrhizic Acid given orally for 8 weeks. Clinical tests in seven normal individuals given oral Ammonium Glycyrrhizate at 6 g/day for 3 days revealed reduced renal and thermal sweat excretion of Na+ and K+, but carbohydrate and protein metabolism were not affected. Glycyrrhetinic Acid at concentrations up to 6% was not a skin irritant or a sensitizer in clinical tests. Neither Glycyrrhizic Acid, Ammonium Glycyrrhizate, nor Dipotassium Glycyrrhizate at 5% were phototoxic agents or photosensitizers. Birth weight and maternal blood pressure were unrelated to the level of consumption of Glycyrrhizic Acid in 1049 Finnish women with infants, but babies whose mother consumed > 500 mg/wk were more likely to be born before 38 weeks. The Cosmetic Ingredient Review (CIR) Expert Panel noted that the ingredients in this safety assessment are not plant extracts, powders, or juices, but rather are specific chemical species that may be isolated from the licorice plant. Because these chemicals may be isolated from plant sources, however, steps should be taken to assure that pesticide and toxic metal residues are below acceptable levels. The Panel advised the industry that total polychlorobiphenyl (PCB)/pesticide contamination should be limited to not more than 40 ppm, with not more than 10 ppm for any specific residue, and that toxic metal levels must not contain more than 3 mg/kg of arsenic (as As), not more than 0.002% heavy metals, and not more than 1 mg/kg of lead (as Pb). Although the Panel noted that Glycyrrhizic Acid is cytotoxic at high doses and ingestion can have physiological effects, there is little acute, short-term, subchronic, or chronic toxicity and it is expected that these ingredients would be poorly absorbed through the skin. These ingredients are not considered to be irritants, sensitizers, phototoxic agents, or photosensitizers at the current maximum concentration of use. Accordingly, the CIR Expert Panel concluded that these ingredients are safe in the current practices of use and concentration. The Panel recognizes that certain ingredients in this group are reportedly used in a given product category, but the concentration of use is not available. For other ingredients in this group, information regarding use concentration for specific product categories is provided, but the number of such products is not known. In still other cases, an ingredient is not in current use, but may be used in the future. Although there are gaps in knowledge about product use, the overall information available on the types of products in which these ingredients are used and at what concentration indicate a pattern of use. Within this overall pattern of use, the Expert Panel considers all ingredients in this group to be safe.
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PMID:Final report on the safety assessment of Glycyrrhetinic Acid, Potassium Glycyrrhetinate, Disodium Succinoyl Glycyrrhetinate, Glyceryl Glycyrrhetinate, Glycyrrhetinyl Stearate, Stearyl Glycyrrhetinate, Glycyrrhizic Acid, Ammonium Glycyrrhizate, Dipotassium Glycyrrhizate, Disodium Glycyrrhizate, Trisodium Glycyrrhizate, Methyl Glycyrrhizate, and Potassium Glycyrrhizinate. 1761 33