Toxicity chronic/subacute

Lithium toxicity (chronic, subacute, or acute) can be secondary to any factor that reduces body clearance, or secondary to acute or sustained elevated doses (and therefore plasma levels) (342). The degree of toxicity can be classified as follows ... 

The pathological effects and clinical signs for many toxic materials can vary with the route and type (acute, single dose vs chronic, subacute doses) of exposure. For the trichothecene mycotoxins, however, a number of the toxic responses are similar, regardless of the route of exposure. As we discussed earlier in this chapter, once they enter the systemic circulation, trichothecene mycotoxins affect rapidly proliferating tissue regardless of the... 

Data on acute toxicity, subacute toxicity, chronic toxicity, teratogenicity, and other toxicity ... 

Intracutaneous reactivity Systemic toxicity (acute) Subacute/subchronic toxicity Genotoxicity Implantation Hemocompatibility Chronic toxicity Carcinogenicity Reproductive toxicity Biodegradation Toxicokinetics Immunotoxicity... 

The health effects of sorbic acid and sorbates have been reviewed (165—167). The extremely low toxicity of sorbic acid enhances its desirabiHty as a food preservative. The oral LD q for sorbic acid in rats is 7—10 g/kg body weight compared to 5 g/kg for sodium chloride (165—169). In subacute and chronic toxicity tests in rats, 5% sorbic acid in the diet results in no abnormal effects after 90 days or lifetime feeding studies. A level of 10% in rat diets results in a slight enlargement of the Hver, kidneys, and thyroid gland (170). This same dietary level fed to mice also resulted in an increase in Hver and kidney weight... 

Health and Safety Factors. Carbonyl sulfide is dangerously poisonous, more so because it is practically odorless when pure. It is lethal to rats at 2900 ppm. Studies show an LD q (rat, ip) of 22.5 mg/kg. The mechanism of toxic action appears to iavolve breakdowa to hydrogea sulfide (36). It acts principally on the central nervous system with death resulting mainly from respiratory paralysis. Little is known regarding the health effects of subacute or chronic exposure to carbonyl sulfide a 400-p.g/m max level has been suggested until more data are available (37). Carbon oxysulfide has a reported inhalation toxicity in mice LD q (mouse) = 2900 ppm (37). 

Scientific information for the process of establishing OELs may come from human or animal data obtained using different methods, from studies of acute, subacute, and chronic toxicity through various routes of entry. Human data, which is usually the best source, is not easily available, and frequently it is incomplete or inadequate due to poor characterization of exposure and clear dose-response relationships. Human data falls into one of the following categories ... 

Subacute and chronic toxicity of alcohol and alcohol ether sulfates has been extensively tested in several animals and sometimes humans. The duration of the tests was in some cases as long as 2 years. When administered below the toxic amount no specific damages were observed in any of the species tested [333]. No severe side effects were observed in the study by Swisher, carried out with volunteers who ingested considerable amounts of anionic and nonionic surfactants over long periods [348]. Similarly, the effects produced by the intake of daily doses of 1 g of alcohol sulfate per person over 8 weeks [349],... 

Toxicological Chronic toxicity Carcinogenicity Fertility study (multi-generation) Embryotoxicity (non-rodent) Acute/subacute toxicity in 2nd species Toxicokinetics... 

The single-dose toxicity studies were performed in two mammalian species, rat and mouse, by the route used in clinical practice, that is oral, as well as that ensuring adequate systemic exposure to the drug, that is intravenous. The subacute (3 months) toxicity studies were correctly carried out in the two animal species (rat, dog) in which also the pharmacokinetics was studied. Since in accordance with the International Conference on Harmonization (CPMP/ICH/286/95), 3-month toxicity studies support clinical trials for up to 1 month s duration (the longest duration of drug administration in clinical use), chronic toxicity studies have not been performed. 

Borelli G, Bertoli D Acute, subacute, chronic toxicity and mutagenicity studies of rifaximin (L/105) in rats. Chemioterapia (Florence)... 

The germanium derivative of cysteine Ge[SCH2CH(NH2)COOH]4 shows low toxicity in acute (3402 mg kg-1), subacute and chronic experiments53. No teratogenic effects were noticed in rats and mice after subcutaneous administration of the compound54. 

Amphotericin B is generally preferred as initial therapy in patients with rapidly progressive disease, whereas azoles are generally preferred in patients with subacute or chronic presentations. Lipid formulations of amphotericin B have not been extensively studied for coccidioidomycosis but can offer a means of giving more drug with less toxicity. Treatments for primary respiratory disease (mainly symptomatic patients) are 3- to 6-month courses of therapy. 

Acute toxicity should be determined in three species subacute or chronic studies should be by the route to be used clinically. Suitable mutagenicity studies should also be... 

Category Duration of Human Administration Clinical Phase Subacute or Chronic Toxicity Special Studies... 

Repeat-dose toxicity (subacute and chronic trials) ... 

These so-called subacute or subchronic toxicity studies involve the repeated application of a test substance to animals, typically for a period of 30 or 90 days. The time pattern is thus an intermediate one between acute and chronic toxicity. To test a substance for subacute or subchronic toxicity, it is mainly applied by ingestion or inhalation. Not one out of the large number of organic pigments which have thus been tested has demonstrated any irreversible toxic effect. No toxic response was observed in rats which were fed either Pigment Yellow 1 or Pigment Yellow 57 1 for 30 days [22],... 

One of the prime concerns, apart from acute and subacute toxicity, is the question of whether a product causes chronic effects. In this context, carcinogenicity studies are of cardinal importance. A possible chronic hazard may be indicated by epi-demological studies. Where such investigations are not available, experiments are performed on animals for the duration of their entire life span. The type of application depends on the exposition (perorally, dermally, per inhalation). 

The term repeated dose toxicity comprises the adverse general (i.e., excluding reproductive, genotoxic, or carcinogenic effects) toxicological effects occurring as a result of repeated daily dosing with, or exposure to, a substance for a part of the expected life span (subacute or subchronic exposure) or for the major part of the fife span, in case of chronic exposure (EC 2003). 

The terms subacute, subchronic, and chronic are often used in the context of repeated dose toxicity. These terms are not used consistently however, there is consistency in the use of the terms subchronic and chronic by OECD, US-EPA, and EU, see below. 

D. Data on acute, subacute and chronic toxicity, teratogenicity and other types of toxicity... 

Reinhart WE, Donati E, Green EA The subacute and chronic toxicity of 1,1-dimethvlhydrazine vapor. Am Ind Hya Assoc 7 21 207-210, 1960... 

Oberst FW, Comstock CC, Hackley EB Inhalation toxicity of ninety per cent hydrogen peroxide vapor—acute, subacute, and chronic exposures of laboratory animals. AMA Arch Ind Hyg Occup Med 10 319-327, 1954... 

Sriramachari S, Jeevaratnam K Comparative toxicity of methyl isocyanate and its hydrolytic derivatives in rats. II. Pulmonary histopathol-ogy in the subacute and chronic phases. Arch Toxicol 69 )-A5-5, 1994... 

Chronic toxicity Rodent and nonrodent species for > 6 months. Required when drug is intended to be used in humans for prolonged periods. Usually run concurrently with clinical trials. Determine same end points as subacute toxicity tests. 

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