Safety Assessment of Polyene Group as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) reviewed the safety of polyenes, which are reported to function in cosmetics primarily as film formers and viscosity increasing agents. The Panel reviewed relevant data related to these ingredients, not inggaps in the available safety data for some of the polyenes in this safety assessment. The data available for many of the ingredients are sufficient and can be extrapolated to support the safety of the entire group because of the similarities in the chemical structures, chemical properties, use concentrations, and reported functions across the group. The Panel concluded that polyenes were safe in cosmetics in the present practices of use and concentration described in this safety assessment.

Final report of the cosmetic ingredient review expert panel on the safety assessment of Polyisobutene and Hydrogenated Polyisobutene as used in cosmetics.

Polyisobutene and Hydrogenated Polyisobutene are homopolymers of isobutene. These ingredients are produced in a wide range of molecular weights. Polybutene is a chemically related cosmetic ingredient previously determined to be safe as used in cosmetic products. Polyisobutene is used in cosmetic products as a binder, film former, and nonaqueous viscosity-increasing agent. Hydrogenated Polyisobutene functions as a skin-conditioning agent-emollient and nonaqueous viscosity-increasing agent with a wide range of uses in cosmetic formulations. The estimated octanol water partition coefficient for Hydrogenated Polyisobutene and Polybutene is log K(ow) of 13.27 and the estimated water solubility was 5.6 x 10(-3) ng/L for Hydrogenated Polyisobutene and Polybutene. Acute oral toxicity testing demonstrated no effects other than lethargy in one rat study. The oral LD(50) was > 5.0 g/kg in rats. No short-term or subchronic animal toxicity data were available. A 2-year chronic oral toxicity study of Polybutene revealed no gross or microscopic pathological changes, and no changes in body weights or food consumption, hematological results, urology, or tumor formation that could be correlated with Polybutene ingestion, except that in the 20,000 ppm group, three out of six males that died between weeks 17 and 24 exhibited hematuria. In a 2-year chronic oral toxicity study of Polybutene in Beagle dogs, no abnormalities in body weight, food consumption, survival, behavioral patterns, hematology, blood chemistry, urinalysis, liver function, gross and histopathologic examinations, or organ weights and ratios were reported. In a three-generation reproductive study in Charles River albino rats that ingested Polybutene, none of the animals in successive generations differed from controls with regard to weight gain, litter size, the number of stillborn, and the number of viable pups during lactation. The survival, body weights, and reactions of test animals were comparable to those of controls. Neither Polyisobutene nor Hydrogenated Polyisobutene were ocular irritants, nor were they dermal irritants or sensitizers. Polyisobutene was not comedogenic in a rabbit ear study. Polyisobutene did not induce transformation in the Syrian hamster embryo (SHE) cell transformation assay, but did enhance 3-methylcholanthrene-induced transformation of C3H/10T1/2 cells. In a carcinogenicity study in mice, Polyisobutene was not carcinogenic, nor did it promote the carcinogenicity of 7,12-dimethylbenz(alpha)anthracene. Clinical patch tests uncovered no evidence of dermal irritation and repeat-insult patch tests with a product containing 4% Hydrogenated Polyisobutene or 1.44% Hydrogenated Polyisobutene found no reactions greater than slight erythema. These products also were not phototoxic or photoallergenic. The product containing 4% Hydrogenated Polyisobutene was not an ocular irritant in a clinical test. The Cosmetic Ingredient Review (CIR) 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 indicate a pattern of use, which was considered by the Expert Panel in assessing safety. Although there is an absence of dermal absorption data for Polyisobutene and Hydrogenated Polyisobutene, the available octanol water partition coefficient data and the low solubility in water suggest very slow absorption, so additional data are not needed. Gastrointestinal absorption is also not a major concern due to the low solubility of these chemicals. Although one in vitro study did report that Polyisobutene did promote cellular transformation, a mouse study did not find evidence of tumor promotion. Because lifetime exposure studies using rats and dogs exposed to Polybutene failed to demonstrate any carcinogenic or tumor promotion effect, and a three-generation reproductive/developmental toxicity study produced no adverse effects, the CIR Expert Panel does not believe these large, mostly insoluble polymers present any risks in the practices of use and concentration as described in this safety assessment.

Assessment of the mechanism of astrocyte swelling induced by the macrolide immunosuppressant sirolimus using multinuclear nuclear magnetic resonance spectroscopy.

The toxic effect of the macrolide immunosuppressant sirolimus on cell metabolism of primary astrocytes was studied by multinuclear NMR spectroscopy of viable cells and perchloric acid (PCA) extracts and compared to the effects of the immunosuppressant cyclosporine. The addition of 5 mg/L sirolimus (5.5 mumol/L) induced swelling of primary astrocytes to 110% of the original volume. Alteration in astrocyte volume in the presence of sirolimus was accompanied by reduction of the following important cell osmolytes and amino acid metabolites: myo-inositol, -58 +/- 12% (mean +/- standard deviation, n = 5); taurine, -44 +/- 5%; glutamine, -13 +/- 2%; compared with control. Sirolimus altered glucose metabolism and partially inhibited the tricarboxylic acid (TCA) cycle: sigma TCA/sigma glycolyse = 1.36 +/- 0.09 (control, n = 3), 0.96 +/- 0.08 (with sirolimus). The increased concentration of phosphodiesters by sirolimus addition (glycerophosphoethanolamine, 52 +/- 18%; glycerophosphocholine, 61 +/- 14%; compared with control, n = 5) indicated disorders in phospholipid metabolism of cellular membranes. Addition of sirolimus led to a decline of the energy state in astrocytes: the concentration of phosphocreatine (PCr) decreased to 75% of control value within 60 min of perfusion with sirolimus and the nucleotide triphosphate (NTP) concentration to 85% within 90 min (n = 3). The effect of sirolimus on the cell metabolism of astrocytes equals that of the immunosuppressants cyclosporine and tacrolimus, the neurotoxicity of which is well-established in clinical studies. The results of this in vitro study indicate that sirolimus possesses neurotoxic potential as well.

Genotoxicity assessment of the antifungal antibiotic aureofungin in Salmonella typhimurium and Swiss albino mice.

The widely used agricultural antifungal agent aureofungin (ARF) was subjected to genotoxicity assessment using the Ames Salmonella assay as well as the in vivo micronucleus test and dominant lethal test in Swiss mice. In the Ames Salmonella spot test, ARF slightly elevated the number of histidine revertants after metabolic activation over a wide dose range (1-1000 micrograms/plate) in TA102 but not in TA97a, TA98 or TA100. In the preincubation plate incorporation assay with TA102, ARF increased the number of revertants in a dose-dependent manner only after metabolic activation. ARF failed to significantly elevate the frequency of micronucleated polychromatic erythrocytes (PE) in the bone marrow of Swiss mice. It elevated the frequency of dominant lethal mutations in the 7th and 8th weeks at 30 mg/kg body weight, a concentration much higher than the actual concentration used in the field. We conclude that ARF is non-mutagenic in somatic cells in vivo at doses used in the present study, probably mutagenic in stem-cell spermatogonia and may be classified as an equivocal promutagen, possibly acting as a cross-linker.

Quantitative assessment of the genotoxicity of fecapentaenes.

Fecapentaenes are a group of fecal mutagens of microbial origin isolated from human stools. Fecapentaene-12 (F-12) and fecapentaene-14 (F-14), differing only in two carbon atoms in the side chain, are glyceryl ethers with a highly reactive chromophoric aliphatic side chain incorporating a conjugated pentaene moiety. Although these compounds are known for their genotoxicity, no test systems have been developed to precisely assess their relative genotoxicity. In this study F-12 and F-14 were assayed for their genotoxicity using the SOS Chromotest in which the induction of beta-galactosidase in E. coli PQ37 was used as a quantitative measure of biological activity. The activity obtained with F-12 and F-14 was compared with that of 4-nitroquinoline oxide (4-NQO) as the reference standard of a direct acting mutagen. While F-14 was almost as active as 4-NQO, F-12 was only about 25% as active as F-14, the higher analog.