Toxicity of the ingredients

Preclinical studies must be performed before an ingredient can be considered for clinical studies in humans in order to determine the potential toxicity of the ingredient and its metabolites and their effects in the matrix. Preclinical studies allow researchers to expose cell cultures and experimental animals to doses of ingredients not normally encountered in human consumption. Results of such assessments are used to determine the threshold of toxicity for the given ingredient (i.e., the margin of safety). 

Because in vitro studies are generally less complex than whole-animal studies, elucidation of an ingredient s metabolic pathway and toxicity characteristics may be facilitated. Different doses of the solubilized ingredient can be incubated with either confluent or preconfluent cells cultured in 10-cm dishes or 96-wells plates to establish uptake and toxicity levels of both the ingredient and its metabolic byproducts. Time-course and dose-response experiments should be conducted to check the growth characteristics of the cells and the toxicity of the ingredient. The production of metabolites can also be followed upon adding... 

Daylight fluorescent pigments (qv) are considered to be nontoxic. Since they are combinations of polymers and dyestuffs, the combined effect of the ingredients must be taken into account when considering the net toxic effect of these materials. Table 5 gives results of laboratory animal toxicity tests of standard modified melamine—formaldehyde-type pigments, the Day-Glo A Series, and the products recommended for plastic mol ding, Day-Glo Z-series. 

Solders. Modem dental solders are made from mostly corrosion-resistant, nontoxic metals. Minimal quantities of tin and other elements are often added, some of which could produce toxic effects in the unalloyed state. Each solder is used for specific appHcations (180—188) typical compositions and properties of solders used in dentistry are presented in Table 11. Most of the ingredients of solders are resistant to corrosion, and alloying them with other ingredients renders the alloy safe for use in appHances placed in the oral environment. Silver solders corrode, but are used only for temporary appHances. Available products do not contain cadmium, although cadmium was an ingredient of some silver solders up to ca 1980. 

Each of the ingredients is chosen with a view to obtaining high clarity at a moderate cost. In Formula 3 the stabilising system has been replaced by a less powerful, but also less toxic, stabiliser. 

Color additives are naturally and synthetically derived. In the past 20 years, consumers have become increasingly aware of the ingredients in their foods and they desire foods be as natural as possible. This fact combined with technological developments have fueled the increases in uses of naturally derived colors. Moreover, additives must be safe and stable in food matfices. Legislation has established which colorants may be used as food additives, taking into account toxicity of compounds and methods of assessment. The European Union currently allows the use of 13 naturally derived colors but 26 colors are exempt from certification... 

Watkins had made no tests whatsoever to assess the toxicity of either the separate ingredients or the combination of ingredients in the final formula (21, 22). He later stated that there was no point in making tests, since the action of the ingredients was well understood (22 ). The glycols, related to glycerine, had been widely used by drug companies, and, Watkins averred, were well known not to be toxic. 

As provided in the Botanical Guidance, clinical studies have been permitted for many botanical preparations prior to a complete set of conventional animal toxicity testing. The decisions were not difficult for submissions with substantial and well-documented history of past human use. But some other applicants had not presented an adequate summary of the past human experiences and had failed even to document well-known toxicity of the herbal ingredients. Between these two extremes, how to adjust the requirements of animal toxicity data and substitute that with large quantity but poor quality of human experiences is another big challenge to the regulatory agency in the review of botanical applications. 

The importance of the inert ingredience in the above formulations is evident. The end-user of the product should be aware of the toxicity of these ingredients. 

If a mixture is diluted with a substance that has an equivalent or lower toxicity classification than the least toxic original ingredient, and which is not expected to affect the toxicity of other ingredients, then the new mixture may be classified as equivalent to the original mixture. Alternatively, the formula explained in paragraph 3.1.3.6.1 could be applied. 

If the total concentration of the ingredient(s) with unknown acute toxicity is < 10% then the formula presented in 3.1.3.6.1 should be used. If the total concentration of the ingredient(s) with unknown toxicity is >10%, the formula presented in 3.1.3.6.1 should be corrected to adjust for the total percentage of the unknown ingredient(s) as follows ... 

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