Subacute or Chronic Toxicity

Statistically or biologically significant changes in clinical or enzyme chemistry (e.g., neurotoxic esterase inhibition, cholinesterase inhibition, or peroxisome proliferation) are reportable. Statistically or biologically significant 

One basic problem in applying the EPA s guidances has been that studies that determine the no observed effect level (NOEL) of a substance always result in some observed effect as a result of the study chemical. The EPA addressed this problem in the Kimm Letter by advising results are not generally 

If the NOELs are lower than these values, the reports should be considered for reporting even if they are based on general, non-specific effects, taking into account the severity of the effect, whether there was a dose response, and other factors that support a finding of a substantial risk. 

Skin and eye irritation studies are not generally reportable if the test substance is expected to be an irritant because its pH is less than three (a strong acid) or greater than eleven (a strong base), or if the test substance has particles that are rough. Reportability depends on the severity of the observed response, and unexpectedly severe responses maybe reportable. Reportability also depends on the potential for exposure. If there is a low potential for exposure because the substance is a research and development chemical, will be used only in low concentrations, or will be used in a closed system, the studies generally are not reportable unless workers will be exposed anyway.  

Sensitization is a systemic response, and studies showing strong sensitization should be reported without regard to potential exposure. Less severe effects can be balanced against the potential exposure. ERA has said that moderate sensitization is not immediately reportable if observed in chemicals that have a low potential exposure because they are research and development chemicals, or they will be used in low concentrations, or they will be used in a closed system. However, EPA recommends reevaluating the reporting decision if the chemical is later used in a different manner with a greater potential for exposure. In practice it is difficult to track chemicals and 

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

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 ... 

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... 

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],... 

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 ... 

No review of subacute, subchronic, or chronic toxicity of chemical warfare nerve agents would be complete without discussion of the significant paper by Munro et al. that reviewed both animal and human studies of the nerve agents tabun (GA), sarin (GB), and VX. These studies included subacute, subchronic, and chronic toxicity studies in animals. Special attention was paid to the phenomenon of Organophosphorus-Induced Delayed Neuropathy (OPIDN). Reproductive toxicity and carcinogenicity tests were reviewed as well as in vitro studies of mutagenicity. Munro et al. s findings can be summarized as follows ... 

The Federal Office of Public Health (FOPH) classifies chemical substances in terms of acute oral toxicity in the rat, and other available data such as skin and/or inhalation toxicity, skin and eye irritation/corrosive effects, subacute/subchronic/chronic toxicity, carcinogenicity/mutagenicity/teratogenicity and human exposure. Substances are placed in one of 5 classes ranging from Category 1 (most hazardous) to Category 5 (least hazardous). 

Subacute and chronic toxicity Subacute and chronic toxicity testing are required for most agents, especially those intended for chronic use. Tests are usually conducted for at least the amount of time proposed for human application, ie, 2-4 weeks (subacute) or 6-24 months (chronic), in at least two species. 

Pb(CH3)4 administered to mice by Intraperitoneal Injection Is converted Into trimethyllead species. The LD50 value In mice is given as 14.3 mg/kg [37]. In the muscle of mice, intoxicated subacutely or chronically with Pb(CH3)4, morphological anomalies concerning mostly the inner part of the blood vessels, sarcoplasmic reticulum, and mitochondria are observed [82]. The effect of microparticles from pyrolysis of Pb(CH3)4 and other antiknock compounds on lungs of mice was Investigated [62]. For studies of intoxication In mice by Pb(CH3)4, see also [8]. The toxicity of Pb(CH3)4 solutions to mice and other animals In combination with other compounds, mainly fuel additives, was studied [20, 25, 26]. 

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). 

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 ... 

Chronic toxicity Rodent and non-rodent species. 6 months or longer. Required when drug is intended to be used in humans for prolonged periods. Usually run concurrently with clinical trial. Goals of subacute and chronic tests are to show which organs are susceptible to drug toxicity. Tests as noted above for subacute. 3 dose levels plus controls. 

In the prediction of long-term "no effect" doses there are two important concepts to consider. One is that there are predictable dose relationships between acute, subchronic and chronic toxic effects. Acute toxicity tests refers to studies wherein single or repeated doses are studied 14 days or less. Subchronic (subacute) tests refers to studies wherein the doses are given five-seven days per week for 90 days, Subchronlc studies are also referred to as 13-week, three-month or short-term tests. 

Toxicity test procedure in higher animals (e.g., rats, mice, rabbits, dogs, and monkeys) is different from that in lower animals because the number of available animals usually is limited. As mentioned earlier, it is not economical or practical to use a few hundred mammals for the evaluation of a single toxicity test. The limitation in number has necessitated several adjustments to assure the validity of toxicity determinations in higher animals. Typically, in the pesticide industry, three types of tests are required acute, subacute, and chronic. 

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