Subacute and chronic toxicity

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... 

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],... 

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... 

Toxicological studies—acute, subacute, and chronic toxicity carcinogenicity ... 

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 ... 

For organic compounds, evaluation of their environmental impact based on data for acute toxicity to fish and estimation of biochemical oxygen demand has been steadily replaced by the results of experiments on subacute and chronic toxicity, sophisticated investigations of microbial metabolism, and an appreciation of the true complexity of partitioning processes. It may... 

Ellis HV et al., Subacute and chronic toxicity studies of trinitroglycerin in dogs, rats, and mice, Fundam. Appl. Toxicol., 4, 248, 1984. 

J.B. Brouwer Food flavorings and compounds of related structure. B. Subacute and chronic toxicity Food Cosmet. Toxicol. 5 (1967) 141-157. 7A03. 

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. 

Acute toxicity studies in two animal species are required by the FDA for all new drugs prior to their use in humans. Subacute and chronic toxicity studies are required for drugs that are intended for chronic systemic use. Toxicity testing in animals usually involves the determination of lethal dose, monitoring of blood, hepatic, renal, and respiratory functions, gross and histopathologic examination of tissues, and tests of reproductive effects and potential carcinogenicity. 

In May 1980, Notification 698 from the MHW specified the type of data required for the evaluation of safety in animals and Guidelines for Toxicity Studies were subsequently established in 1984. It is necessary to generate data on acute, subacute and chronic toxicity, effect on reproduction, dependence, antigenicity, mutagenicity, carcinogenicity, and local irritation. 

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