Local toxicity tests

Many drugs, including many biopharmaceuticals, are administered to localized areas within the body by, for example, s.c. or i.m. injection. Local toxicity tests appraise whether there is any associated toxicity at/surrounding the site of injection. Predictably, these are generally carried out by s.c. or i.m. injection of product to test animals, followed by observation of the site of injection. The exact cause of any adverse response noted (i.e. active ingredient or excipient) is usually determined by their separate subsequent administration. 

Corrective Action Application In Massachusetts, a municipal wastewater treatment plant receives a number of wastestreams containing heavy metals from local industries. When tested, the dewatered sludge failed the EP toxicity test. In order to permit landfill disposal of the sludge, solidification processes were examined. A soluble, silicate-based system, developed by Chemfix, was ultimately selected which produced a product whose leachate passed the EP toxicity test (Sullivan, 1984). 

There has been considerable progress in developing in vitro tests (a.25). The most success has been in local effects testing in biologically less complex systems, such as testing for skin and eye irritation. In contrast, efforts to develop in vitro tests to evaluate potential systemic toxicants have been hindered by the complexity of the systems involved, and it seems likely that a battery of different in vitro assays will be needed. 

In Japan, Uchiyama has recently published requirements for the safety evaluation of new excipients. These requirements include studies on acute, subacute, and chronic toxicity, mutagenicity, effects on reproduction, dependency, antigenicity, carcinogenicity, and local irritation (human patch test). The first five of these tests are mandatory. With the exception of the local irritation test, for which a domestic trial is required, non-Japanese data are acceptable for these studies. Even if a material has been used in a pharmaceutical product outside Japan, the material is treated as a new excipient if there has been no prior use in Japan, although relevant overseas data for the material are acceptable for regulatory submission. A material is treated as a new excipient when the route of administration differs or the dose level exceeds that of prior use even after approval for the Japanese market.f ... 

Several entries in this encyclopedia address eye and skin toxicology, and the testing approaches used to assess irritation as an endpoint. The most progress in the development of nonanimal procedures has been for the assessment of local toxicity, for example, eye and skin corrosion and irritation, and many alternatives to animal testing are now available to assess the eye and skin corrosion and irritation potentials of... 

Spain Effluent toxicity testing is undertaken on a regional basis. There is no national regulatory requirement but legally enforceable conditions can be set locally. 

Surber, C., and U. C. Dubach. 1989. Tests for local toxicity of intramuscular drug preparations. Comparison of in vivo and in vitro findings. Arzeneimittel-Forschung 39 1586-1589. 

All electrical devices should be turned off except for the necessary ventilation pumps. Local gas tests should be performed before and during any welding or other hot work. Exposure to toxic substances should be recorded and the proper fresh air should be supplied to all underground areas. 

There are several standards that medical polymers must adhere to. One of the most common standards observed for polymeric materials is published by the United States Pharmacopeia (USP), which necessitates using animal models (in vivo) to test toxicity of elastomers, plastics, and other polymeric materials, prior to clinical use. The standard and forms of testing it outlines is considered in the medical industry as the minimum requirement for a polymeric material before it is considered for use in healthcare applications. According to the standard the biological response of the test animals are measured and determined via three main techniques (1) Systemic toxicity test Evaluates the effects of leachables of intravenously or intraperitoneally injected materials on systems such as the nervous or immune system (2) Intracutaneous test Evaluates local response to materials injected under the skin (3) Implantation test Both local tissue microscopic and macroscopic parameters evaluated at material implant sites. 

Until now only the saponin adjuvant QS-21 (3) has entered vaccine clinical trials. Saponin mixtures causing local toxicity and hemolytic activity such as Quil A, have not yet been tested in clinical trials of human vaccines. After preclinical trials of QS-21 in rabbits, dogs, rhesus monkeys and baboons, this molecule was evaluated in phase 1 clinical trials of experimental melanoma immunotherapeutic vaccines, of HIV-1 subunit vaccines and more recently of a promising malaria vaccine [34-36]. 

Because most fluorinated surfactants are commercial products containing several components, the toxicity of impurities in fluorinated surfactants has to be considered. Commercial fluorinated surfactants are usually sold as solutions in an aqueous solvent [10]. In some cases, the solvent may cause more systemic or local toxic effects than the surfactant itself. The solvent and volatile impurities may dominate the toxic effects produced by inhalation. Nonionic surfactants with a poly(oxyethylene) hydrophilic chain may contain 1,4-dioxane, which has shown carcinogenic activity in some animal tests. 1,4-Dioxane is a by-product found in nonionic surfactants, regardless of whether the surfactants are fluorinated. However, the concentration of 1,4-dioxane in nonionic surfactants is carefully controlled and is usually very low (about 0.1% or less). Air monitoring has indicated that at a workplace where there are nonionic fluorinated surfactants containing about 0.1 % dioxane, the 1,4-dioxane concentration in air would be below 1 ppm. 

Acute Toxicity Studies. These studies should provide the following information the nature of any local or systemic adverse effects occurring as a consequence of a single exposure to the test material an indication of the exposure conditions producing the adverse effects, in particular, information on dose—response relationships, including minimum and no-effects exposure levels and data of use in the design of short-term repeated exposure studies. 

Melamine ia a skin test on rabbits produced neither local irritation nor systemic toxicity. As a 10% solution ia methylceUulose, it caused no irritation ia the eyes of rabbits. Human subjects were given patch tests with melamine. No evidence of either primary irritation or sensitization was found. Such results suggest that melamine crystal may be handled ia ordinary iadustrial use without special hygienic precautions. 

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