General Toxicity
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III.C.0.1 III.C.0.2 III.C.1 III.C.1.1 III.C.2 III.C.2.1 III.C.2.2 III.C.2.3 III.C.2.4 III.C.2.5 III.C.2.6 III.C.2.6.1 III.C.2.6.2 III.C.2.6.3 III.C.2.7
Acute Toxicity . . . . . . . . . . . . . . . . . . Subacute and Chronic Toxicity Studies . . . . . . . . . . . . . . . . . . . . . . . . . Subacute and Chronic Studies for Recombinant Proteins . . . . . . Carcinogenicity Testing . . . . . . . . . . Testing for Skin Irritation . . . . . . Draize Test . . . . . . . . . . . . . . . . . . . . . . Testing for Irritation of Mucosal Membranes . . . . . . . . . . . . . . . . . . . . . Testing for Dermal Sensitization . Photo Toxicity . . . . . . . . . . . . . . . . . . Photosensitization . . . . . . . . . . . . . . . Local Tolerance Testing for Parenteral Drugs . . . . . . . . . . . . . . . . Intra-Arterial Testing . . . . . . . . . . . . Intramuscular Testing . . . . . . . . . . . . Sub-cutaneous Testing . . . . . . . . . . . Toxicological Testing of Biotechnologically Produced Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . .
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time between administration, onset, and disappearance of toxic signs can provide valuable information about the toxic-kinetic behavior of the compound (Dekant and Vamvakas 1994). Testing of combination of drug substances gives information about additive, over-additive or underadditive toxic effects of the combination partners. The method of determination has changed in the last three decades mainly for animal welfare reasons. Producing mortality in animals in order to determine an LD50 (dosis letalis media) is no longer the main purpose of acute toxicity testing. Today, acute toxicity focuses on levels of acute tolerance, nature of acute toxic symptoms in the sub-lethal range, and dose levels which cause mortality in few animals, i.e. quality has replaced quantity. This principle can be followed by using 3–5 animals per sex and dosage group. PROCEDURE
Drug Substance
799
III.C.0.1 Acute Toxicity PURPOSE AND RATIONALE
Acute toxicity testing determines the toxicity of a chemical/drug substance after single administration using different routes of administration (oral, dermal, sub-cutaneous, intra-venous, intra-peritoneal, via inhalation = pulmonary). The main purpose of acute toxicity studies is to evaluate the degree of toxicity in a quantitative and qualitative manner with the purpose of comparing it with other drug substances (e.g. other drug candidates for the same indication). Further, acute toxicity testing provides information about the acute toxic effects of a chemical in a qualitative manner i.e. it generates information about acute mechanisms of toxicity. Another purpose is to develop first ideas about dose levels to be tested in studies with multiple administrations (sub-chronic, chronic studies). The
For toxicity testing, the quality of the drug substance should be similar to that intended to be used in clinical trials, and, after approval, to that for marketing purposes, i.e. the pattern of impurities should be simila
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