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Consumer product manufacturers utilise a spectrum of alternative ocular irritation assays, as these tests do not require the use of live animals. Despite their usefulness, no regulatory-accepted assay assesses the reversibility of ocular damage, a key criterion of GHS ocular classification, like the rabbit eye test (i.e., Draize Rabbit Eye Test [DRET]). The Porcine Corneal Opacity Reversibility Assay (PorCORA), an ex vivo intact corneal tissue culture model, predicts the reversibility of damage by ocular irritants. Inclusion of the damage reversibility endpoint in the PorCORA supplements other alternative test methods for ocular irritation, by assessing induced eye damage and the ability of this damage to reverse (heal) without the use of live animals to distinguish between Globally Harmonised System of Classification and Labelling of Chemicals (GHS) ocular classifications. In this focused study, results of a Bovine Corneal Opacity and Permeability (BCOP) test of a laundry detergent, neat and 10% dilution, (product mixture from S.C. Johnson & Son, Inc. [SCJ]) classified the product into GHS Category 1; however, the BCOP test cannot assess the reversibility of ocular damage. The laundry detergent was evaluated using the PorCORA, where ocular damage induced by the detergent was fully reversed within seven days. Evaluation of the reversibility of ocular damage using the PorCORA in this focused study can add strength to the weight-of-evidence (WoE) analysis approach in ocular hazard assessment. This WoE approach strengthens the argument that the PorCORA can be used to supplement BCOP data, and that this laundry detergent is not an irreversible eye irritant. [ABSTRACT FROM AUTHOR]

OptiSafeTM (OS) is a shelf stable, nonanimal test for ocular irritation. A recent database search found that half of the OS false positive (FP) materials were associated with reactive oxygen chemistries but were not eye irritants in vivo (based on historical rabbit studies by other groups). We hypothesized that naturally occurring tear antioxidants protect the eye from reactive chemistries in vivo and that specific tear chemistries might help explain why some materials are FP for nonanimal tests but are reported as nonirritants in the live animal. To test this hypothesis, a prior study evaluated tear antioxidants and found that the tear antioxidant ascorbic acid, added at human physiological tear levels to the OS test, specifically reduced the measured values for these FPs but did not reduce the true-positive rate. Based on these findings, the OS test method was further optimized. The purpose of the current study was to comprehensively evaluate the performance of the further optimized test method for detection of ocular irritants. The OS test measures chemically induced damage to macromolecules and relates these measured values to ocular irritancy. To improve the performance of OS, we made updates to the material to be tested physiochemical handling procedures, prediction model, and test method to include tear-level concentrations of ascorbic acid. We then retested the 78 chemicals from the prior OS-coded validation study in triplicate and compared the accuracy of the 'nonirritant versus irritant' prediction for the further optimized method with the prior results. We report that for the detection of 'nonirritant' versus 'irritant' (GHS NC versus categories 2B/A and 1) test substances, the further optimized OS test with ascorbic acid compared with the original version has a FP rate that is reduced from 40.0 to 22.2%, the false-negative (FN) rate remains at 0.0%, and the accuracy improved from 80.3% to 89.2%. A comparison to OECD-adopted tests demonstrates that the further optimized OS test, like the original method, has a higher accuracy and lower FN rate for the detection of 'nonirritants' versus 'irritants' (GHS Category NC versus 2B/A and 1) than the other eye irritation tests (BCOP, EpiOcularTM Eye Irritation Test, ICE, Ocular Irritection®, and STE). [ABSTRACT FROM AUTHOR]

OptiSafe is an in chemico test method that identifies potential eye irritants based on macromolecular damage following test chemical exposure. The OptiSafe protocol includes a prescreen assessment that identifies test chemicals that are outside the applicability domain of the test method and thus determines the optimal procedure. We assessed the usefulness and limitations of the OptiSafe test method for identifying chemicals not requiring classification for ocular irritation (i.e. bottom-up testing strategy). Seventeen chemicals were selected by the lead laboratory and tested as an independent study. Ninety-five unique coded chemicals were selected by a validation management team to assess the intra- and interlaboratory reproducibility and accuracy of OptiSafe in a multilaboratory, three-phased validation study. Three laboratories (lead laboratory and two naïve laboratories) evaluated 35 chemicals, with the remaining 60 chemicals evaluated by the lead laboratory only. Test method performance was assessed by comparing classifications based on OptiSafe results to classifications based on available retrospective in vivo data, using both the EPA and GHS eye irritation hazard classification systems. No prospective in vivo testing was conducted. Phase I testing of five chemicals showed that the method could be transferred to naïve laboratories; within-lab reproducibility ranged from 93% to 100% for both classification systems. Thirty coded chemicals were evaluated in Phase II of the validation study to demonstrate both intra- and interlaboratory reproducibility. Intralaboratory reproducibility for both EPA and GHS classification systems for Phase II of the validation study ranged from 93% to 99%, while interlaboratory reproducibility was 91% for both systems. Test method accuracy for the EPA and GHS classification systems based on results from individual laboratories ranged from 82% to 88% and from 78% to 88%, respectively, among the three laboratories; false negative rates ranged from 0% to 7% (EPA) and 0% to 15% (GHS). When results across all three laboratories were combined based on the majority classification, test method accuracy and false negative rates were 89% and 0%, respectively, for both classification systems, while false positive rates were 25% and 23% for the EPA and GHS classification systems, respectively. Validation study Phase III evaluation of an additional 60 chemicals by the lead laboratory provided a comprehensive assessment of test method accuracy and defined the applicability domain of the method. Based on chemicals tested in Phases II and III by the lead laboratory, test method accuracy was 83% and 79% for the EPA and GHS classification systems, respectively; false negative rates were 4% (EPA) and 0% (GHS); and false positive rates were 40% (EPA) and 42% (GHS). Potential causes of false positives in certain chemical (e.g. ethers and alcohols) or hazard classes are being further investigated. The OptiSafe test method is useful for identifying nonsurfactant substances not requiring classification for ocular irritancy. OptiSafe represents a new tool for the in vitro assessment of ocular toxicity in a tiered-testing strategy where chemicals can be initially tested and identified as not requiring hazard classification. [ABSTRACT FROM AUTHOR]

Objective: Propylene glycol (PG) is a widely used solvent, chemical intermediate and carrier substance for foods, pharmaceutical and cosmetic products. Professional and occupational exposure to PG aerosol and vapor may occur from theatrical smoke generators and during application of deicing products to airplanes. While PG is considered to have low toxicity, the results of one study suggested that brief (1-min) exposure to PG mist elicited ocular and respiratory effects in humans. Because the high concentrations and brief exposure duration in that study were not representative of most occupational exposures, a controlled experimental exposure study was conducted to clarify or confirm the earlier findings. Materials and methods: Ten males and 10 females were exposed to PG aerosol for 4 hrs at 20 and 100 mg/m3 and 30 min at 200 mg/m3. Total PG exposure concentrations (droplets plus gas phase) were 95.6, 442.4 and 871 mg/m3 for the three conditions, respectively. Participants rode a stationary bicycle to simulate physical effort at regular intervals during exposure. Objective measures evaluated in this study included ocular irritation via eye blink task and eye photography and pulmonary function via spirometry, while subjective measures included health symptoms ratings, irritation and dryness ratings of eyes, nose, throat and mouth. Results: Objective measures of pulmonary function and ocular irritation did not reveal any exposure-related changes. Exposure-related changes in symptom reporting were observed; however, the highest symptom ratings did not exceed “slight” on the scale. Conclusions: The results indicate at the concentrations and acute durations tested, PG does not affect human respiratory function or produce ocular irritation. [ABSTRACT FROM AUTHOR]

The successful ophthalmic delivery system is reliant on the diminution in the precorneal loss of drugs by increasing the corneal contact time and increasing the transcorneal permeability, which may enhance the bioavailability of drug to the eyes. The objective of this investigation was to develop and evaluate the potential of microemulsions of gatifloxacin with respect to the conventional eye drops of gatifloxacin. Oil-in-water microemulsions were prepared with different concentrations of oil, surfactant and co-surfactant using aqueous titration method. All formulations showed circular shape droplets, displayed an average droplet size ranged between 51 and 74 nm and absolute zeta potential values ranged from 15 to 24 mV, with optimum physicochemical characteristics suitable for eye. The optimized microemulsion possessed good stability, showed greater adherence to corneal surface and good permeation of gatifloxacin in the anterior chamber of the eye, resulting in a twofold increase in gatifloxacin concentration than the conventional dosage form. Hence, the optimized microemulsions showed increased intraocular penetration and enhance ocular bioavailability of gatifloxacin. [ABSTRACT FROM AUTHOR]

Objective: To explore the use of oleic acid (OA) in ocular drug delivery. Methods: Six compounds, namely rhodamine B, sodium-fluorescein, fluorescein isothiocyanate (FITC) dextrans of 4, 10, 20 and 40 kDa were selected as model drugs. The effect of OA on the corneal permeability of drugs was evaluated in vitro, using isolated rabbit corneas by a Franz diffusion cell. The safety of OA was assessed on the basis of corneal hydration level. The ocular irritation of OA was also tested in rabbits in vivo using the Draize eye test. Results: In the presence of OA, at a concentration of 0.02-0.1%, the maximum increase in the apparent permeability coefficient (Papp) was 3.21-, 1.76- and 1.57-fold for rhodamine B, sodium-fluorescein and FITC-dextran of 4 kDa, respectively. However, no significant permeability enhancement of FITC-dextrans of 4, 10, 20 and 40 kDa was found in the presence of OA. It enhanced the corneal penetration of model compounds in a concentration-dependent manner. The Papp values of rhodamine B decreased with increasing concentration of OA, while the Papp values of sodium-fluorescein and FITC-dextrans of 4 kDa increased. The Papp enhanced by 0.1% OA was logarithmically correlated to the molecular weight of model drugs ( R2 = 0.9991). With the 0.02%, 0.05% and 0.1% oleic application, the corneal hydration values were <83%, and Draize scores were <4. Conclusion: OA may have potential clinical benefits in improving the ocular drug delivery of both hydrophilic and lipophilic compounds. [ABSTRACT FROM AUTHOR]

The purpose of this study was to develop an ophthalmic drug delivery system for cyclosporine A (CsA) based on glyceryl monooleate (GMO)/poloxamer 407 liquid crystalline nanoparticles with reduced ocular irritancy and improved corneal penetration. CsA-loaded liquid crystalline nanoparticles were prepared via fragmentation of a bulk GMO/poloxamer 407 cubic phase gel by high-pressure homogenization and characterized. Corneal permeation and retention was evaluated using modified Franz diffusing cells. Intra-corneal transportation was investigated with fluorescein isothiocyanate (FITC)-labeled liquid crystalline nanoparticles. Ocular irritation was then evaluated using the Draize method. The mean particle size of liquid crystalline nanoparticles was 193.5 nm and the entrapment efficiency was 95.11 ± 0.67%. A bicontinuous cubic phase of cubic P-type was determined using cryo-transmission electron microscopy (cryo-TEM) observation and small angle X-ray diffraction (SAXD) analysis. A 1.52-fold increase in J s and a 2.2-fold increase in corneal retention was achieved by liquid crystalline nanoparticles compared with oil solution. In vitro corneal permeation investigated with FITC-labeled liquid crystalline nanoparticles revealed that CsA penetrated across the cornea under the transportation of liquid crystalline nanoparticles. Liquid crystalline nanoparticles exhibited excellent ocular tolerance in the ocular irritation test. This low-irritant vehicle based on liquid crystalline nanoparticles might be a promising system for effective ocular CsA delivery. [ABSTRACT FROM AUTHOR]

Methazolamide (MTA) is an antiglaucoma drug; however, there are many side effects of its systemic administration with insufficient ocular therapeutic concentrations. The aim of this study was to formulate MTA-loaded solid lipid nanoparticles (SLNs) and evaluate the potential of SLNs as a new therapeutic system for glaucoma. SLNs were prepared by a modified emulsion--solvent evaporation method and their physicochemical characteristics were evaluated. The pharmacodynamics was investigated by determining the percentage decrease in intraocular pressure. The ocular irritation was studied by Draize test. Despite a burst release of SLNs, the pharmacodynamic experiment indicated that MTA--SLNs had higher therapeutic efficacy, later occurrence of maximum action, and more prolonged effect than drug solution and commercial product. Formulation of MTA--SLNs would be a potential delivery carrier for ocular delivery, with the advantages of a more intensive treatment for glaucoma, lower in doses and better patient compliance compared to the conventional eye drops. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the use of Labrasol in ocular drug delivery system. Methods: The in vivo ocular irritation of Labrasol was tested by pathological section observation using rabbits. The effects of Labrasol on corneal permeability of baicalin was investigated in vitro, using isolated rabbit corneas. The pharmacokinetics was evaluated by microdialysis in the rabbit aqueous humors. Results: The results of the ocular irritation studies showed that Labrasol was non-irritant at the concentrations studied (0.5–3.0%(v/v)), while Labrasol produced slight irritation at a concentration of 5.0%(v/v). For the in vitro study, with Labrasol at concentrations of 1.5%, 2.0%, and 3.0%(v/v), the apparent permeability coefficient ( Papp) was 1.69-, 3.14-, and 2.23- fold of baicalin solution, respectively. In the pharmacokinetics studies, the AUC value of baicalin solution with 2.0% and 3.0%(v/v) Labrasol were 4.7- and 5.6-fold of that of the control group ( p < 0.01), and the Cmax value of baicalin solution with 2.0% and 3.0%(v/v) Labrasol vs the control group were 3.2- and 5.7-fold ( p < 0.01). Conclusion: Labrasol may have potential clinical benefits in improving the ocular drug delivery of baicalin. [ABSTRACT FROM AUTHOR]

The aim of this study was to explore the use of Pharmasolve® as a new kind of permeability enhancer in ophthalmic drug delivery systems. The ocular irritation of different concentrations of Pharmasolve® on rabbit eyes was evaluated in detail. Four drugs ranging from hydrophilic to lipophilic, namely ribavirin, puerarin, enoxacin, and ibuprofen, were used as model compounds to investigate the effects of different concentrations of Pharmasolve® on the corneal permeability. The mechanism of ocular permeation enhancement of drugs by Pharmasolve® was also discussed. The results showed that Pharmasolve® presented no irritation when the concentration used was lower than 10%. Pharmasolve® could enhance the ocular permeability of the four test drugs; the maximum enhancement in P app was 4.04, 2.76, and 2.67-fold for ribavirin, enoxacin, and puerarin, respectively; 2.5% (v/v) Pharmasovle® increased the P app by about 1.47-fold for ibuprofen; which suggested that it would have a great potential to be used as a safe and effective penetration enhancer in ocular drug delivery systems in the future. [ABSTRACT FROM AUTHOR]

We have evaluated the ocular irritancy potential of an unknown environmental contaminant, para-toluene sulfonic acid (pTSA), compared with that of known irritants, 5% sodium dodecyl sulfate (SDS) and 10% acetic acid (AA), using a simplified, ex vivo rabbit eye test modified to measure cytotoxicity as a mechanistic correlate to the Draize rabbit eye test. Rabbit eyes were obtained fresh within 24 hours from an abattoir and then exposed to 50 μL of test material. Eyes were then incubated intact for 3 hours or 1 day, and the corneas were removed, stained with calcein acetoxymethylester (AM)/ethidium homodimer ( assay, Invitrogen Corp., Carlsbad, CA, USA), and evaluated by laser scanning confocal microscopy. The number of dead cells was then quantified and the difference was statistically compared. For corneas exposed to 1 ppm and 1% pTSA, there was no significant difference in the number of dead cells compared with water-exposed, control corneas at either 3 hours or 1 day after exposure. However, corneas exposed to 10% and 50% pTSA showed significantly increased (p < .0001) numbers of dead cells, averaging (mean ± standard deviation) 486 ± 133 and 1,052 ± 101 cells/field of view (460 × 460 μm). The level of cytotoxicity was comparable with that observed for 10% AA, which averaged 409 ± 142 cells/field of view. The data suggest that pTSA is an innocuous irritant at exposure levels environmentally encountered, but that higher concentrations (10% and above) might be considered a slight to mild irritant. We conclude that this modified ex vivo rabbit eye test using the assay may be a useful model for developing ocular irritation assays. [ABSTRACT FROM AUTHOR]

A large database has demonstrated a robust relationship between the chorioallantonic membrane (CAM) and the Draize rabbit eye tests. The precision, sensitivity, and direct correlation of the CAM with human eye evaluations were critically appraised in this work. A total of 24 studies, including 12 CAM assays and 12 human clinical studies were conducted. Both the CAM assay and the human tests demonstrated good interassay precision and a robust correlation between the CAM scores and the inflammatory responses of human eye bulbar conjunctiva, palpebral conjunctiva and scleral vessels. This provided sound evidence that the CAM assay could be a predictive screen for eye irritation assessment for personal wash products and a key element of the tiered scientific approach in supporting labeling claims such as "tear free". [ABSTRACT FROM AUTHOR]

We have characterized 22 ocular irritants differing in type (surfactants, acid, alkali, bleaches, alcohol, aldehyde, acetone) and severity (slight to severe) by using the low-volume rabbit eye test. Ocular irritation was evaluated by 1) light microscopy to assess pathological changes, 2) in vivo confocal microscopy (CM) to quantify 4-dimensionally (x, y, z, and t) initial corneal injury and later responses in the same eye, and 3) laser scanning CM to quantify initial cell death. These studies revealed that regardless of the processes leading to injury, slight irritants injure the corneal epithelium, mild irritants injure the corneal epithelium and the superficial stroma, and moderate/severe irritants injure the epithelium, deep stroma, and at times the corneal endothelium. Furthermore, extent of initial corneal injury was shown to predict subsequent responses and final outcomes. These findings suggest that extent of corneal injury may be used as a basis for the development of alternative ocular irritation tests. To test the validity of this approach, we have used an ex vivo , rabbit cornea culture model to measure extent of corneal injury following exposure to ocular irritants. Data indicate that the extent of ex vivo corneal injury significantly correlate with the extent of initial injury measured previously in live animals. Overall, these findings indicate that extent of initial corneal injury can be used as a new “gold standard” for the continued refinement and ultimate replacement of the Draize rabbit eye Ocular Irritation Test. [ABSTRACT FROM AUTHOR]

Bacillus thuringiensis var. kenyae (B.t.k.) is a microbial insecticide effective against lepidopteran pest species. Acute oral toxicity in rats and acute dermal toxicity, ocular irritation, skin irritation in rabbits were studied for the wettable powder formulation of B.t.k. In addition, toxicity of the wettable powder formulation was also studied in fresh water fish (Gambussia affinis). The results of these studies indicate that this wettable powder formulation of B.t.k. is nontoxic and nonirritant to rats, rabbits, and fish. [ABSTRACT FROM AUTHOR]

Hemoglobin denaturation was used as a test method to evaluate the potential ocular irritation induced by surfactants in four categories: anionic, cationic, nonionic, and amphoteric and manufactured productscontaining surfactants. We have proposed a plot representation of the results in order to determine the irritation potential of a substance. The results obtained by this method were compared to the Draize ocular test in vivo. A good correlation was found between the results obtained in vitro and in vivo for some of the surfactants and manufactured products. There was one false-negative result among the surfactants. Two surfactants and one manufactured product produced false-positive results. The method is easy, rapid, economical, and provides enough information about the possible irritant action of surfactants and manufactured products with surfactants in their formulation. Nevertheless, the method is not completely satisfactory and it is necessaryto perform more than one alternative method to enhance the safety ofnew product. The main problem of this test method is the color interference of some products at determined concentrations. [ABSTRACT FROM AUTHOR]