In Silico Prediction of Eye Irritation Using Hansen Solubility Parameters and Predicted pKa Values.

An in silico method has been developed that permits the binary differentiation between pure liquids causing serious eye damage or eye irritation, and pure liquids with no need for such classification, according to the UN GHS system. The method is based on the finding that the Hansen Solubility Parameters (HSP) of a liquid are collectively important predictors for eye irritation. Thus, by applying a two-tier approach in which in silico-predicted pKa values (firstly) and a trained model based solely on in silico-predicted HSP data (secondly) were used, we have developed, and validated, a fully in silico approach for predicting the outcome of a Draize test (in terms of UN GHS Cat. 1/Cat. 2A/Cat. 2B or UN GHS No Cat.) with high validation set performance (sensitivity = 0.846, specificity = 0.818, balanced accuracy = 0.832) using SMILES only. The method is applicable to pure non-ionic liquids with molecular weight below 500 g/mol, fewer than six hydrogen bond donors (e.g. nitrogen-hydrogen or oxygen-hydrogen bonds) and fewer than eleven hydrogen bond acceptors (e.g. nitrogen or oxygen atoms). Due to its fully in silico characteristics, this method can be applied to pure liquids that are still at the desktop design stage and not yet in production.

An alternative predictor of eye irritation that utilizes potential parameters of the human corneal epithelium model calculated based on Hansen solubility parameters.

Eye irritation predictions are very important in the development of cosmetics and pharmaceuticals. For animal protection, alternative tests are being developed to replace the Draize test, which involves the use of rabbits to test eye irritation. The Vitrigel-eye irritancy test (Vitrigel-EIT), is one such alternative. As a preliminary study, we evaluated if Hansen solubility parameter (HSP) values can be used to predict Vitrigel-EIT results. An Hansen sphere was created based on the HSP values and Vitrigel-EIT results from 61 substances. Substances inside and outside of the sphere were designated as dangerous and safe substances, respectively. The safety of each test substance was predicted by comparing the center point (Ro) of the sphere with the relative energy difference, i.e., the ratio of each test substance (Ra). The accuracy, false negativity, and false positivity of the "irritant" and "nonirritant" designations, as determined by the Vitrigel-EIT results and Hansen sphere, were 91.8% (56/61), 2.3% (1/43), and 22.2% (4/18), respectively. These results indicated that HSP values can be used to predict Vitrigel-EIT results with high reproducibility, and thus are useful for evaluating the safety of substances.

Lack of peripheral neuropathy in Beagle dogs after 53 weeks oral administration of thalidomide capsules.

Thalidomide (Thalomid) is approved for use in the US to treat complications from leprosy. Peripheral neuropathy is a dose-limiting adverse event in humans. As part of a nonrodent regulatory toxicology study, Beagle dogs were fed orally via encapsulation for 53 weeks. A component of this study was to determine if the dogs developed peripheral neuropathy. Twenty-eight male and 28 female Beagle dogs approximately 8-10 months of age were used. They were dosed at 43, 200 or 1000 mg/kg for 53 weeks followed by a 4-week treatment-free recovery period. Nerve function was assessed by electrophysiological measurements of the tibial nerve prior to dosing and at weeks 13, 27, 38 and 51. Representative dogs from each group were sacrificed at 26, 53 and 58 weeks and histologic and ultrastructural evaluations were performed on the sural nerve. Thalidomide had no effect on sensory nerve conduction velocity, duration or amplitude of the action potential. At 27 weeks, mean sensory nerve action potential amplitude for females at 43 mg/kg was significantly greater than control but was not evident at 39 weeks. Mean duration of sensory nerve action potential seemed to increase with similar magnitude over time in all dose groups including controls. Histological and ultrastructural evaluation of sections of sural nerve did not identify treatment-induced differences between control and thalidomide-dosed animals after 26 and 53 weeks of treatment. Additionally, no differences were observed following a 5-week treatment-free period at week 58. In contrast to humans, Beagle dogs did not develop thalidomide-induced peripheral neuropathy under conditions of the study.