Dermal Toxicity Studies Research Articles

Effect of particle dimension on biocompatibility of carbon nanomaterials

With various emerging applications ranging from medicine to materials and electronics, the risk of exposure to nanomaterials is rapidly increasing. Several routes of exposure to nanomaterials exist; the most important being dermal contact and inhalation. In this dermal toxicity study, the cellular effects of carbon-based materials with diameters ranging from micro- to nano-dimension were investigated using mouse keratinocytes (HEL-30). The carbon materials tested included carbon fibers (CF; 10 μm diameter), carbon nanofibers (CNF; 100 nm diameter), multi-walled carbon nanotubes (MWCNT; 10 nm diameter), and single-walled carbon nanotubes (SWCNT; 1 nm diameter). CF and CNF did not significantly affect cell viability; however, MWCNT and SWCNT reduced cell viability in a time-dependent manner up to 48 h, with full recovery of mitochondrial function by the 72 h time point. After a 24 h exposure, cells exposed to MWCNT produced up to 3-fold higher increase in reactive oxygen species than those exposed to SWCNT. The results of this study suggest that high-aspect ratio carbon material toxicity is dependent on dimension and composition.

Hydrolysis of a series of parabens by skin microsomes and cytosol from human and minipigs and in whole skin in short-term culture

Parabens are esters of 4-hydroxybenzoic acid and used as anti-microbial agents in a wide variety of toiletries, cosmetics and pharmaceuticals. It is of interest to understand the dermal absorption and hydrolysis of parabens, and to evaluate their disposition after dermal exposure and their potential to illicit localised toxicity. The use of minipig as a surrogate model for human dermal metabolism and toxicity studies, justifies the comparison of paraben metabolism in human and minipig skin. Parabens are hydrolysed by carboxylesterases to 4-hydroxybenzoic acid. The effects of the carboxylesterase inhibitors paraoxon and bis-nitrophenylphosphate provided evidence of the involvement of dermal carboxylesterases in paraben hydrolysis. Loperamide, a specific inhibitor of human carboxylesterase-2 inhibited butyl- and benzylparaben hydrolysis in human skin but not methylparaben or ethylparaben. These results show that butyl- and benzylparaben are more selective substrates for human carboxylesterase-2 in skin than the other parabens examined. Parabens applied to the surface of human or minipig skin were absorbed to a similar amount and metabolised to 4-hydroxybenzoic acid during dermal absorption. These results demonstrate that the minipig is a suitable model for man for assessing dermal absorption and hydrolysis of parabens, although the carboxylesterase profile in skin differs between human and minipig.

Development of a base set of toxicity tests using ultrafine TiO 2 particles as a component of nanoparticle risk management

The development of a risk management system for nanoscale or ultrafine particle-types requires a base set of hazard data. Assessing risk is a function of hazard and exposure data. Previously, we have suggested “parallel tracks” as a strategy for conducting nanoparticle research. On the one hand, mechanistic studies on “representative” nanoparticles could be supported by governmental agencies. Alternatively, with regard to commercial nanoparticles, the environmental, health and safety (EHS) framework would include a minimum base set of toxicity studies which should be supported by the companies that are developing nano-based products. The minimum base set could include the following criteria: substantial particle characterization, pulmonary toxicity studies, acute dermal toxicity and sensitization studies, acute oral and ocular toxicity studies, along with screening type genotoxicity, and aquatic toxicity studies. We report here the toxicity results of a base set of hazard tests on a set of newly developed, well-characterized, ultrafine TiO 2 (uf-TiO 2) particle-types. In vivo pulmonary toxicity studies in rats demonstrated low inflammatory potential and lung tissue toxicity. Acute dermal irritation studies in rabbits and local lymph node assay results in mice indicated that uf-TiO 2 was not a skin irritant or dermal sensitizer. Acute oral toxicity studies demonstrated very low toxicity and uf-TiO 2 produced short-term and reversible ocular conjunctival redness in rabbits. Genotoxicity tests demonstrated that uf-TiO 2 was negative in both the bacterial reverse mutation test and in an in vitro mammalian chromosome aberration test with Chinese hamster ovary cells. The results of aquatic toxicity screening studies demonstrated that uf-TiO 2 exhibited low concern for aquatic hazard in unaerated, 48 h, static acute tests using the water flea, Daphnia magna; exhibited low concern for aquatic hazard in unaerated, 96 h, static acute tests using the rainbow trout, Oncorhynchus mykiss; and exhibited medium concern in a 72 h acute test using the green algae Pseudokirchneriella subcapitata. To summarize the findings, the results of most of the studies demonstrated low hazard potential in mammals or aquatic species following acute exposures to the ultrafine TiO 2 particle-types tested in this program.

Repeated dose toxicity and developmental toxicity of diisopropanolamine to rats

The repeated dose oral and dermal toxicity of diisopropanolamine (DIPA) was evaluated in rats and compared to the reported toxicity of the related secondary alcohol amine, diethanolamine (DEA). Fischer 344/DuCrl rats were given up to 750 mg /kg/day by dermal application, 5 days/week, for 4 weeks; or up to 1000 mg DIPA/kg/day by drinking water for 13 weeks to evaluate potential toxic effects. Time-mated female CRL:CD(SD) rats were given up to 1000 mg/kg/day by gavage on gestation days (GD) 6–20 for evaluation of maternal and fetal effects. In the dermal toxicity study, no adverse treatment-related in-life effects other than mild irritation at the site of dermal application at ⩾500 mg/kg/day were observed. There were no systemic effects in rats given up to 750 mg/kg/day. In the subchronic oral toxicity study, the most significant effects were an increase in absolute and relative kidney weights, unaccompanied by histopathologic changes, at ⩾500 mg/kg/day DIPA. The latter effect was ameliorated following a 4-week recovery period. In the developmental toxicity study, there were no maternal or developmental effects at any dose level evaluated. The toxicity of DIPA contrasts with that of DEA which has been shown to affect a number of organ systems when repeatedly administered orally or dermally at similar or lower dosages.

What does a dermal acute toxicity study add to the information on a plant protection pesticide?

What does a dermal acute toxicity study add to the information on a plant protection pesticide?

Characterization of the Skin Penetration of a Hydrocarbon-Based Weapons Maintenance Oil

Break-Free CLP is a commercial petroleum-based liquid used for cleaning, lubricating, and protecting firearms that is used in the United States by military personnel, police, and individual gun owners for maintaining a wide variety of firearms. According to its material safety data sheet (MSDS), Break-Free CLP is predominately polyalphaolefin oil but also contains dibasic ester and isoparaffinic hydrocarbons; all of these ingredients are known to induce skin irritation in laboratory animals. Studies completed in our labs found that repeated topical application of Break-Free CLP to the backs of CD-1 mice produced evidence of systemic effects. Studies were conducted to characterize the dermal penetration of Break-Free CLP in mouse, rat, and pig skin to provide insight on possible factors or causes of skin irritation and systemic effects observed in previous studies. Mouse skin was 37 times more permeable to Break-Free CLP than pig skin and 6 times more permeable than rat skin. Flux measurements from static diffusion cells showed an inverse correlation with mouse, rat, and pig skin thickness. The concentration of Break-Free CLP in mouse skin was 4.5 times higher than the amount found in rat skin and about 17 times higher than the amount absorbed by pig skin. These results support the idea that Break-Free CLP causes skin irritation and systemic effects in the mouse by both penetrating through and accumulating in the skin. The findings for rat and pig skin are probably most representative of Break-Free CLP flux into and through unprotected human skin and suggest that dermal toxicity studies in CD-1 mice overestimate the risk to humans. These results, nevertheless, suggest that persons handling or using Break-Free CLP should protect the skin from possible exposure.

Hydroquinone and its analogues in dermatology – a risk‐benefit viewpoint

Hydroquinone (HQ) has been used since the 1950s in commercially available over-the-counter skin lightener products and since the 1960s as a commercially available medical product. It is also used in cosmetic products such as hair dyes and products for coating finger nails. Beginning in 2001, HQ is no longer authorized for use in cosmetic skin lightening formulations in European Union countries, although products containing arbutin, an analogue of HQ, and botanicals, including plants that naturally contain HQ and arbutin, continue to remain available in European countries. The potential toxicity of HQ is dependent on the route of exposure, and toxicity in rodents is highly sex-, species-, and strain-specific. Subchronic and chronic toxicity in experimental animals is primarily limited to nephrotoxicity in male F-344 rats. Dermal toxicity studies, even those conducted in the sensitive male F-344 rat, are essentially devoid of systemic toxicity. Developmental and reproductive toxicity studies with HQ in rats and rabbits have not demonstrated significant effects. Cancer bioassay data for HQ demonstrate limited effects and are not sufficient to classify HQ for human carcinogenicity. Epidemiology and occupational studies of workers with extensive exposure to HQ have not reported any evidence of adverse systemic health effects or carcinogenicity. A risk-benefit approach is recommended for assessing the available data for HQ, arbutin, and other materials in use as, or proposed for use as, skin lighteners to provide optimal therapeutic benefits to patients with pigmentary changes of the skin.

An experimental in vitro model for dynamic direct exposure of human cells to airborne contaminants

The aim of this study was to establish a dynamic in vitro model for direct exposure of human cells to gaseous contaminants to investigate the cellular responses to airborne chemical exposures. Nitrogen dioxide (NO 2) was selected as a model gas compound. Standard test atmospheres were generated (2.5–10 ppm), using a dynamic direct dilution method. Human cells including: A549 pulmonary type II-like epithelial cell lines and skin fibroblasts were grown on porous membranes. Human cells on snapwell inserts were placed in horizontal diffusion chambers and exposed to various airborne concentrations of NO 2 directly at the air/liquid interface for 1 h at 37 °C. Cytotoxicity of the test gas was investigated using the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium), NRU (neutral red uptake) and ATP (Adenosine triphosphate) assays. Dose-dependent effects of NO 2 were observed in human cells tested which resulted in a significant reduction of cell viability at concentrations normally encountered in workplace environments ( p < 0.05). Our findings suggest that the dynamic direct exposure method can be used for in vitro inhalational and dermal toxicity studies and potentially as an advanced technology for biomonitoring of airborne contaminants in future occupational and environmental toxicity assessments.

Safety studies on epigallocatechin gallate (EGCG) preparations. Part 2: Dermal, acute and short-term toxicity studies

Green tea extract and its principal active ingredient, epigallocatechin gallate (EGCG), are gaining attention and increased usage due to their healthful properties. Despite the increasing demand for these products, few studies have examined their safety. The toxicity of purified green tea extracts containing high concentrations of EGCG have been evaluated in a series of studies in order to define the safety of Teavigo™, a high-concentration EGCG extract produced by the same novel method. Topical EGCG preparations caused minor dermal irritation in rats and guinea pigs, but not rabbits, and was a moderate dermal sensitizing agent in the guinea pig maximization test. A rabbit eye irritation test produced a strong enough response to not warrant any further testing in this assay. An oral dose delivering 2000 mg EGCG preparation/kg was lethal to rats; whereas, a dose of 200 mg EGCG/kg induced no toxicity. The dietary administration of EGCG preparation to rats for 13 weeks was not toxic at doses up to 500 mg/kg/day. Similarly, no adverse effects were noted when 500 mg EGCG preparation/kg/day was administered to pre-fed dogs in divided doses. This dose caused morbidity when administered to fasted dogs as a single bolus dose, although this model was considered an unrealistic comparison to the human condition. From these studies a no-observed adverse effect level of 500 mg EGCG preparation/kg/day was established.

Amended Final Report of the Safety Assessment of Dibutyl Adipate as Used in Cosmetics1

Dibutyl Adipate, the diester of butyl alcohol and adipic acid, functions as a plasticizer, skin-conditioning agent, and solvent in cosmetic formulations. It is reportedly used at a concentration of 5% in nail polish and 8% in suntan gels, creams, and liquids. Dibutyl Adipate is soluble in organic solvents, but practically insoluble in water. Dibutyl Adipate does not absorb radiation in the ultraviolet (UV) region of the spectrum. Dibutyl Adipate is not toxic in acute oral or dermal animal toxicity tests. In a subchronic dermal toxicity study, 1.0 ml/kg day-1 caused a significant reduction in body weight gain in rabbits, but 0.5 ml/kg/day1 was without effect. In a study with dogs, no adverse effects were observed when an emulsion containing 6.25% Dibutyl Adipate was applied to the entire body twice a week for 3 months. Dibutyl Adipate was tested for dermal irritation using rabbits and mice and a none to minimal irritation was observed. Dibutyl Adipate at a concentration of 25% was not a sensitizer in a guinea pig maximization study. Undiluted Dibutyl Adipate was minimally irritating to the eyes of rabbits and 0.1% was nonirritating. A significant increase in fetal gross abnormalities was observed in rats given intraperitoneal injections of Dibutyl Adipate at 1.75 ml/kg on 3 separate days during gestation, but no effect was seen in animals given 1.05 ml/kg. Dibutyl Adipate was not genotoxic in either bacterial or mammalian test systems. Clinical patch tests confirmed the absence of skin irritation found in animal tests. Clinical phototoxicity tests were negative. Dibutyl Adipate at 0.1% was not an ocular irritant in two male volunteers. In a clinical test of comedogenicity, Dibutyl Adipate produced no effect. The Cosmetic Ingredient Review (CIR) Expert Panel recognized that use of Dibutyl Adipate in suntan cosmetic products will result in repeated, frequent exposure in a leave-on product. The available data demonstrate no skin sensitization or cumulative skin irritation, no comedogenicity, and no genotoxicity. Combined with the data demonstrating little acute toxicity, no skin or ocular irritation, and no reproductive or developmental toxicity, these data form an adequate basis for reaching a conclusion that Dibutyl Adipate is safe as a cosmetic ingredient in the practices of use and concentrations as reflected in this safety assessment.

A novel in vitro exposure technique for toxicity testing of selected volatile organic compounds

Exposure to vapours of volatile chemicals is a major occupational and environmental health concern. Toxicity testing of volatile organic compounds (VOCs) has always faced significant technological problems due to their high volatility and/or low solubility. The aim of this study was to develop a practical and reproducible in vitro exposure technique for toxicity testing of VOCs. Standard test atmospheres of xylene and toluene were generated in glass chambers using a static method. Human cells including: A549-lung derived cell lines, HepG2-liver derived cell lines and skin fibroblasts, were grown in porous membranes and exposed to various airborne concentrations of selected VOCs directly at the air/liquid interface for 1 h at 37 degrees C. Cytotoxicity of test chemicals was investigated using the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) and NRU (neutral red uptake) assays following 24 h incubation. Airborne IC(50) (50% inhibitory concentration) values were determined using dose response curves for xylene (IC(50)=5350+/- 328 ppm, NRU; IC(50)=5750+/- 433 ppm, MTS in skin fibroblast) and toluene (IC(50)=0 500+/- 527 ppm, NRU; IC(50)=11,200 +/- 1,044 ppm, MTS in skin fibroblast). Our findings suggest that static direct exposure at the air/liquid interface is a practical and reproducible technique for toxicity testing of VOCs. Further, this technique can be used for inhalational and dermal toxicity studies of volatile chemicals in vitro as the exposure pattern in vivo is closely simulated by this method.

Final Report of the Safety Assessment of Niacinamide and Niacin1

Niacinamide (aka nicotinamide) and Niacin (aka nicotinic acid) are heterocyclic aromatic compounds which function in cosmetics primarily as hair and skin conditioning agents. Niacinamide is used in around 30 cosmetic formulations including shampoos, hair tonics, skin moisturizers, and cleansing formulations. Niacin is used in a few similar product types. The concentration of use of Niacinamide varies from a low of 0.0001% in night preparations to a high of 3% in body and hand creams, lotions, powders and sprays. Niacin concentrations of use range from 0.01% in body and hand creams, lotions, powders and sprays to 0.1% in paste masks (mud packs). Both ingredients are accepted for use in cosmetics in Japan and the European Union. Both are GRAS direct food additives and nutrient and/or dietary supplements. Niacinamide may be used in clinical treatment of hypercholesteremia and Niacin in prevention of pellegra and treatment of certain psychological disorders. Both ingredients are readily absorbed from skin, blood, and the intestines and widely distribute throughout the body. Metabolites include N1-methylnicotinamide and N1-methyl-4-pyridone-3-carboxamide. Excretion is primarily through the urinary tract. While Niacinamide ismore toxic than Niacinin acute toxicity studies, both are relatively non-toxic. Short-term oral, parenteral, or dermal toxicity studies did not identify significant irreversible effects. Niacinamide, evaluated in an in vitro test to predict ocular irritation, was not an acute ocular hazard. Animal testing of Niacinamide in rabbits in actual formulations produced mostly non-irritant reactions, with only some marginally irritating responses. Skin irritation tests of up to 2.5% Niacinamide in rabbits produced only marginal irritation. Skin sensitization tests of Niacinamide at 5% during induction and 20% during challenge were negative in guinea pigs. Neither cosmetic ingredient was mutagenic in Ames tests, with or without metabolic activation. Niacinamide and Niacin at 2 mg/ml were negative in a chromosome aberration test in Chinese hamster ovary cells, but did produce large structural chromosome aberrations at 3 mg/ml. Niacinamide induced sister chromatid exchanges in Chinese hamster ovary cells, but Niacin did not. Under certain circumstances, Niacinamide can cause an increase in unscheduled DNA synthesis in human lymphocytes treated with UV or a nitrosoguanidine compound. Niacinamide itself was not carcinogenic when administered (1%) in the drinking water of mice. No data on the carcinogenic effect of Niacin were available. Niacinamide can moderate the induction of tumors by established carcinogens. Niacinamide in combination with streptozotocin (a nitrosourea compound) or with heliotrine (a pyrrolizidine alkaloid), produced pancreatic islet tumors. On the other hand, Niacinamide reduced the renal adenomas produced by streptozotocin; and intestinal and bladder tumors induced by a preparation of bracken fern. Niacinamide evaluated in in vitro test systems did affect development, but Niacinamide reduced the reproductive/developmental toxicity of 2-aminonicotinamide-amino-1,3,4-thiadiazole hydrochloride and urethane. Clinical testing of Niacinamide produced no stinging sensation at concentrations up to 10%, use tests produced no irritation at concentrations up to 5%, and a 21-day cumulative irritation test at concentrations up to 5% resulted in no irritancy. Niacinamide was not a sensitizer, nor was it a photosensitizer. The CIR Expert Panel considered that Niacinamide and Niacin are sufficiently similar from a toxicologic standpoint to combine the available data and reach a conclusion on the safety of both as cosmetic ingredients. Overall, these ingredients are non-toxic at levels considerably higher than would be experienced in cosmetic products. Clinical testing confirms that these ingredients are not significant skin irritants, sensitizers or photosensitizers. While certain formulations were marginal to slight ocular irritants, other formulations were not. Niacinamide, while not carcinogenic alone, can modulate the induction of tumors by certain established carcinogens. The Panel noted that the doses in these studies are high relative to the low concentrations at which Niacinamide is used in cosmetic formulations. In neither case (tumor protection or tumor promotion) are these findings considered relevant to the use of Niacinamide at its current low concentrations of use in cosmetics. Both ingredients were considered safe as used in cosmetics.

Enhanced Transdermal Delivery of Local Anesthetics by Liposome Formulation of Local Anesthetic Mixture

Various concentrations of either lidocaine or tetracaine, plus combinations of lidocaine and tetracaine were formulated into liposomes to improve topical anesthesia. The topical anesthetic effects of these liposomal mixtures of local anesthetics (Lipo-MLA) were then compared with those of EMLA (Eutectic Mixture of Local Anesthetics) and single local anesthetic liposomes using a pinprick test on healthy adult volunteers. The Lipo-MLA exhibited significantly improved anesthetic effects compared to the EMLA and single local anesthetic liposomes with a faster onset time of approximately thirty minutes and duration of at least four hours. A dermal toxicity study using rats revealed that Lipo-MLA was safe at greater than 2,000 mg/kg bodyweight.

Safety of a Novel Botanical Extract Formula for Ameliorating Allergic rhinitis. Part II

Each year more than 50 million Americans suffer from allergic rhinitis, which is a state of hypersensitivity or hyperimmunity. Basically, allergic rhinitis is symptomatically recognized as the inflammation and irritation of the nasal mucosal membranes; sneezing; stuffy/runny nose; nasal congestion; and itchy; watery, and swollen eyes; and defined as a state of hypersensitivity/ hyperimmunity caused by exposure to a particular allergen (antigen) that results in increased reactivity upon subsequent exposure. A novel polyherbal formulation (Aller-7/NR-A2) was developed for the treatment of allergic rhinitis using a unique combination of extracts from seven medicinal plants, including Phyllanthus emblica, Terminalia chebula, Terminalia bellerica, Albizia lebbeck, Piper nigrum, Zingiber officinale, and Piper longum. Earlier studies in our laboratories have demonstrated potent antihistaminic, anti-inflammatory, antispasmodic, antioxidant, and mast-cell stabilization activities of Aller-7 in addition to its efficacy in a clinical setting. A series of preliminary toxicological evaluations were also conducted in the past, which demonstrated its safety. In this study, we have conducted further safety studies on Aller-7, including acute oral, acute dermal, acute dermal irritation, eye irritation, and 90-day repeated dose toxicity studies. Acute oral toxicity of Aller-7 was found to be greater than 5,000 mg/kg body weight in both male and female rats and no mortality or toxicity was observed at this dose, while the acute dermal toxicity was found to be greater than 2,000 mg/kg body weight. In the acute dermal irritation study, the skin irritancy index was found to be 0.0, which classifies Aller-7 as a nonirritant to rabbit skin. In the acute eye irritation study, Aller-7 was found to have minimal irritancy to eyes of rabbits. In the repeated-dose 90-day oral toxicity study, Aller-7 was administered at dose levels of 100, 300, and 1,000 mg/kg rat body weight for 90 consecutive days by oral gavage. Aller-7 did not induce any significant change in the hematological parameters. No ocular abnormalities were observed. Some minor histopathological changes were observed, but did not reveal any significant treatment-related histopathological changes. The above findings revealed that the no observed adverse effect level (NOAEL) of Aller-7 is greater than 1,000 mg/kg body weight. Taken together, these studies demonstrate the broad spectrum safety of Aller-7.

A review of evidence from short-term studies leading to the prediction that diazoaminobenzene (1,3-diphenyltriazine) is a carcinogen

The National Toxicology Program (NTP) is responsible for providing comprehensive toxicology evaluations of substances, while at the same time incorporating approaches to reduce, refine or replace laboratory animals in routine toxicity/carcinogenicity studies. Consistent with this, a series of metabolism studies in rodents and human liver slices, electron spin resonance spectroscopy (ESR) studies, short-term dermal toxicity studies in rodents, and acute bone marrow micronucleus studies in mice were performed on diazoaminobenzene (DAAB, also known as 1,3-diphenyltriazine). These studies demonstrated that DAAB is metabolized and shares similar genotoxic and toxicological properties to the known human carcinogen, benzene, and the known rodent carcinogen, aniline. These data were used to evaluate the potential carcinogenicity of DAAB without doing a 2-year rodent bioassay. Based on this analysis, DAAB was predicted to be carcinogenic if evaluated in a 2-year rodent bioassay. These data were evaluated to support listing DAAB in the NTP Report on Carcinogens as a substance 'reasonably anticipated to be a human carcinogen'. The purpose of this article is to review the data developed for predicting the carcinogenicity of DAAB.

AOT water-in-oil microemulsions as a penetration enhancer in transdermal drug delivery of 5-fluorouracil

In vitro transdermal permeation of 5-fluorouracil (antineoplastic), a hydrophilic drug encapsulated in AOT/water/isopropylmyristate water-in-oil microemulsions (MEs), were studied using a modified Keshary and Chien diffusion cell. AOT (aerosol-OT or sodium bis(2-ethylhexyl) sulfosuccinate) is an anionic surfactant, which forms ‘water-in-oil’ ME in non-aqueous medium. The effect of water and AOT concentrations in MEs to the transdermal permeation of 5-fluorouracil through hairless mouse skin was investigated. MEs with 5:95 weight ratio of AOT:isopropylmyristate, containing 0.9, 1.8, 2.7 and 3.6% w/w of water have showed 1.68-, 2.36-, 3.58- and 3.77-fold increases in the skin flux of 5-fluorouracil (5-FU) respectively, compared to the aqueous solution of drug. The MEs with 5:95, 9:91 and 13:87 weight ratio of AOT:isopropyl myristate at fixed water content W 0 = 15 ( W 0 = [H 2O]/AOT]) gave 3.58-, 5.04- and 6.3-fold enhancement of drug. In addition, attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy was used to examine the effect of ME on lipid alkyl chain, hydration level, and corneocyte cells of the stratum corneum (SC). Results reveal that the ME interacts with a component of the SC and perturbs its architectural structure. The extent of perturbation in the SC depends on the concentration of water and AOT in the ME. Preliminary dermal toxicity studies indicate that the AOT/water/isopropylmyristate ME be safe for the transdermal permeation of 5-FU.

Safety evaluation of a natural tomato oleoresin extract derived from food-processing tomatoes

Experimental and epidemiological studies indicate that consumption of tomato products containing high amounts of lycopene is associated with lowered cancer risk. The protective effects of lycopene may be related to its antioxidant potential. Lycopene has been demonstrated to inhibit oxidation. A proprietary, natural tomato oleoresin extract (NTOE), is a purified tomato oleoresin containing 6% lycopene produced from tomatoes. NTOE was evaluated for toxicological effects, and found the 50% lethal dose (LD 50), derived from the acute oral toxicity study, was greater than 5000 mg/kg body weight. The no-observed-adverse-effect level (NOAEL) derived from the 13-week study was 4500 mg/kg/day. Acute dermal toxicity study of NTOE found no toxicity at 2000 mg/kg body weight. NTOE lacked dermal irritation in the rabbit model, but was found to have moderate eye-irritant capabilities. NTOE tested at 5% (w/w) in petroleum jelly was a moderate sensitizer in the guinea pig model. There was no evidence of mutagenic potential up to 5000 μg/plate, as determined by the Ames assay. These results demonstrate the inability of NTOE to produce oral, dermal or mutagenic toxicity in animal models at doses greater than 300 times the normal human consumption of lycopene. Consumption analysis of lycopene-containing foods estimated mean daily intake of lycopene at 8.2 mg/day.

Final report on the safety assessment of ethoxyethanol and ethoxyethanol acetate.

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.

Dermatotoxicity in the Hypotrichotic(htr) Rabbit Derived from the Japanese White(JW-NIBS) Strain Rabbit.

Utility of Japanese White rabbit mutants with hypotrichosis (htr strain) was investigated in dermal toxicity studies. In the primary irritation study, the primary irritation indices (P.I.I.) by application of hexachlorophene and 3, 3’, 4’, 5-tetrachlorosalicylanilide (TCSA) were higher in the htr rabbits than in the control, haired rabbits. The P.I.I. by application of Tween 80 and sodium lauryl sulfate (SLS) were similar between the htr rabbits and the control rabbits. In the 16-day cumulative irritation study, irritation scores induced by SLS and sodium hydroxide were lower in the htr rabbits than in the control rabbits throughout the observation periods. However, approximately 30% of the dorsal skin of the control rabbits underwent the anagen phase of the hair cycle during the cumulative periods, resulting in difficulty to apply the chemicals and to estimate the skin reactions. In the phototoxicity study, irritation scores of the htr rabbits treated with 8-methoxypsoralen and TCSA were similar to those of the control rabbits. These results revealed advantages of the htr rabbits in the administration of test chemicals and the evaluation of skin reactions, suggesting the usefulness of htr rabbits for dermal toxicity studies.

Hereditary breast cancer

Wound healing plays a major concern in the field of surgery as it requires uneventful healing. Management aims towards prevention of infection and to accelerate healing. Acharya Sushruta has given more emphasis on Vrana (wound) and its chikitsa (treatment). Many antiseptic agents which prevent infection are widely used but have no role in accelerating the healing process and are cytotoxic, deleterious to wound healing. In this regard an innovative polyherbomineral formulation Pentabark Kashaya (PK)was formulated to assess acute dermal toxicity and woundhealing activity.To explore the wound healing efficacy of novel Ayurveda Formulation i.e Pentabark Kashaya in Wistar rats using the excision wound model.Acute dermal toxicity study was carried out on five female Wistar rats by following the OECD guideline 434 and signs of toxicity were assessed for the period of 14 days. Wound healing activitywas assessed on the excision wound model. 18 male Wistar rats were procured for the study and divided into three groups (n = 6 in each group). The test group was treated with application of PK, standard group with Povidone iodine solution 5% and control group with distilled water. The parameters assessed were epithelialization period, wound contraction rate, wound closure day and swab test for microbial load for the period of 21 days. Statistical analysis was done by using one way ANOVA and Tukeys HSD to assess changes in between three groups at each time point.No signs of acute dermal toxicity were seen, which proved that PK is safe for application. Significant results were seen in the parameters of wound healing like period of epithelialization and wound closure day. Percentage of wound contraction rate was increased in test group when compared to other groups. Histopathology of skin showed marked changes in re-epithelialization, dermal fibroblast, dermal fibrocytes in test group when compared to control group.PK is safe for application and it is effective in wound healing.Clinical Trial Registration No.: Not applicable.