Abstract
Regulatory classification of skin irritation has historically been based on rabbit data, however current toxicology processes are transitioning to in vitro alternatives. The in vitro assays have to provide sufficient level of sensitivity as well as specificity to be accepted as replacement methods for the existing in vivo assays. This is usually achieved by comparing the in vitro results to classifications obtained in animals. Significant drawback of this approach is that neither in vivo nor in vitro methods are calibrated against human hazard data and results obtained in these assays may not correspond to situation in human.The main objective of this review was to establish an extended database of substances classified according to their human hazard to serve for further development of alternative methods relevant to human health as well as resource for improved regulatory classification. The literature has been reviewed to assemble all the available information on the testing of substances in the human 4 h human patch test, which is the only standardized protocol in humans matching the exposure conditions of the regulatory accepted in vivo rabbit skin irritation test.A total of 81 substances tested according to the defined 4 h human patch test protocol were found and collated into a dataset together with their existing in vivo classifications published in the literature. While about 50% of the substances in the database are classified as irritating based on the rabbit skin test, on using the 4 h HPT test, less than 20% were identified as acutely irritant to human skin. Based on the presented data, it can be concluded that the rabbit skin irritation test largely over-predicts human responses for the evaluated chemicals. Correct classification of the acute skin irritation hazard will only be possible if newly developed in vitro toxicology methods will be calibrated to produce results relevant to man.
Highlights
One of the most important advances in regulatory toxicology has been the implementation of the Globally Harmonised System (GHS) for the identification, classification and labelling of substances, mixtures and preparations (United Nations-Economic Commission for Europe, 2009)
The main objective of this review was to establish an extended database of substances classified according to their human hazard to serve for further development of alternative methods relevant to human health as well as resource for improved regulatory classification
While about 50% of the substances in the database are classified as irritating based on the rabbit skin test, on using the 4 h HPT test, less than 20% were identified as acutely irritant to human skin
Summary
One of the most important advances in regulatory toxicology has been the implementation of the Globally Harmonised System (GHS) for the identification, classification and labelling of substances, mixtures and preparations (United Nations-Economic Commission for Europe, 2009). In vitro alternatives have taken the place of the rabbit test and in a similar manner aim at a basic hazard identification of chemicals which can cause burns or a significant level of acute skin irritation (ECHA, 2008b; Eskes et al, 2012; Commission Regulation, 2009). These efforts in regulatory toxicology are directed towards characterisation of the intrinsic properties of substances, with subsequent application of that knowledge to mixtures and Interdisciplinary Toxicology. To obtain controlled human acute skin irritation information, an alternative strategy involving a protocol for the use of human volunteers, the 4 h Human Patch Test (4 h HPT), to characterize skin irritation hazard has been developed and described extensively in the literature (Basketter, 1994; Basketter et al 1994a,b; 1997; York et al 1996; Robinson et al, 2001)
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