Irreversible toxicity

IDLH 25 This concentration poses an immediate danger to life and health (i.e., causes of irreversible toxic effects for a 30-minute exposure). 12... 

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],... 

Nevertheless, the toxicity of fluoroacetate seems to be only partially due to the inhibition of aconitase. The competitive nature of the inhibition, its Xj value (Xj = 20-60 pM)," and the time-dependent nature (but reversible) of the inhibition of aconitase seem to be poorly compatible with the sharp and irreversible toxicity of fluorocitrate. Thus, it has been suggested that fluorocitrate can covalently bind with the proteins that are involved in citrate transport through the mitochondrial membrane. ... 

Solvents to be limited Nongenotoxic animal carcinogens or possible causative agents of other irreversible toxicity such as neurotoxicity or teratogenicity... 

In 1977, the NAS Safe Drinking Water Committee outlined four principles that it said should be useful in dealing with the assessment of hazards that involve chronic irreversible toxicity or the effects of longterm exposure (20). These principles (paraphrased as follows) were intended to apply primarily to cancer risks from substances whose mechanisms involve somatic mutations and may also be applicable to mutagenesis and teratogenesis ... 

Define sublethal effects, reversible effects, and margin of safety. What is an irreversible toxic effect ... 

Less preferred solvents (Class 2) are listed in Table 2. As stated in the ICH document, these solvents need to be limited because they are suspected to be nongenotoxic animal carcinogens or possible causative agents of some irreversible toxicity such as neurotoxicity or teratogenicity. They may also cause other significant, frequently... 

A mechanism of irreversible toxicity of/wnz-chloroamphetamine (PC A, 120a) to serotonergic neurons has recently been proposed. According to this proposal, PCA induces 5HT release from serotonergic neurons. The ability of PCA also to function as a monoamine oxidase inhibitor leads to an accumulation of extraneuronal 5HT. Nonenzymatic oxidation produces the neurotoxin, 6-hydroxy-5HT, which is taken up into the neuron where cross-linking to macromolecular structures leads to neuronal destruction221,222. 

Class 2 solvents are to be limited and include nongenotoxic animal carcinogens and others that induce irreversible toxicity like neurotoxicity and teratogenicity, and solvents suspected of other significant but reversible toxicities (Table 4.3). 

Reversible versus irreversible toxicity Reversible toxic effects are those that can be repaired, usually by a specific tissue s ability to regenerate or mend itself after chemical exposure, while irreversible toxic effects are those that cannot be repaired. 

Evidence of damage to brain, kidney, heart, and lungs have been reported in rabbits exposed acutely to metallic mercury vapor at certain concentrations. Both reversible and irreversible toxic effects may be caused by mercury and its compounds. The rabbit (inhalation) LClo is 29mgm over 30h, and another rat (inhalation) TClo is 4mgm over 2h a day for 11 days. 

Spermatozoa a-Chlorohydrin directly affects spermatozoa with a resultant diminution in motility. Since this direct effect is reversible, a-chlorohydrin was once considered a candidate for male contraception. However, because irreversible toxicity was found in the epididymis, the potential for drug development of a-chlorohydrin was not explored further. The sulfonamide drug sulfasalazine may affect mature spermatozoa in the epididymis, resulting in decreased fertility. However, historical data on... 

Class II solvents Solvents to be limited. These include non-genotoxic animal carcinogens or possible causative agents (e.g., acetonitrile, cyclohexane, toluene, methanol and N,N-dimethylacetamide) of irreversible toxicity such as neurotoxicity... 

In general, chronic toxic effects occur when the agent accumulates in the biological system, when an agent produces irreversible toxic effects, or when there is insufficient time for the system to recover from the toxic effect within the exposure frequency interval. For many agents the toxic effects of acute exposure are quite different from those produced by chronic exposure. According to the site of action, chronic toxic effects can be divided into two groups local, and systemic effects. For some substances both local and systemic effects can be observed. 

Erbstatin and 2,5-MeC also inhibited EGF-induced DNA synthesis in NRK cells (5). In quiescent normal rat kidney cells EGF induces DNA synthesis with a peak at 20 hours. Erbstatin and 2,5-MeC delayed the DNA synthesis for about 3 hours and 8 hours, respectively, without showing irreversible toxicity. 

Rice, J. M., Carcinogenesis A late effect of irreversible toxic damage during development. Env. Health Perspec.,... 

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