Twenty eight-day dietary toxicity study of Luo Han fruit concentrate in Hsd:SD rats.

A 28-day dietary study was conducted in Hsd:SD rats to evaluate the safety of PureLo, a non-caloric powdered concentrate of the Chinese fruit Luo Han Guo, which derives its sweetening properties from triterpene glycosides called mogrosides. Groups of 20 rats (10/sex/group) were fed diets containing 0, 10,000, 30,000, or 100,000 ppm PureLo for 28 days (OECD, Redbook 2000). PureLo was well tolerated and produced no significant adverse effects. Reduced body weight and body weight gain in high-dose animals of both sexes were related to sporadic reductions in food consumption; there were no overall differences in feed efficiency. Statistically significant changes in clinical chemistry (decreased bilirubin, increased total protein) and relative organ weights of liver, adrenals, ovaries and/or testes, and epididymides were not correlated with any histopathological findings and were not considered adverse. Although a few clinical and pathological findings suggest possible treatment-related effects, particularly in the high-dose group, these findings were transient, not dose-dependent, non-adverse, inconsistent, occurred only in one sex, and/or not supported by histopathological findings. Under the conditions of this study and based on the toxicological endpoints evaluated, the NOAEL for PureLo was 100,000 ppm in the diet, the highest level tested, equivalent to 7.07 and 7.48 g/kg bw/day for male and female rats, respectively.

Comparison of estimated daily per capita intakes of flavouring substances with no-observed-effect levels from animal studies.

A study was conducted to determine the margins of safety between no-observed-effect levels (NOELs) and daily per capita intake of flavouring substances evaluated by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) using the safety evaluation procedure for flavouring substances. The safety evaluation procedure provides a practical method for integrating data on intake, structure-activity relationships, metabolism and toxicity to evaluate flavouring substances. The comparison of NOELs to intake reinforces the fact that the margins of safety between intake of flavouring substances and their representative NOELs is very large. 98% of flavouring substances have margins of safety greater than 1000, illustrating that even if intake was underestimated by several fold, in almost every case, a wide margin of safety would still exist.

A procedure for the safety evaluation of flavouring substances. Joint FAO/WHO Expert Committee on Food Additives.

This review describes a procedure for the safety evaluation of flavouring substances. Over 2500 flavouring substances are currently in use in food. While toxicity data do not exist on all flavouring substances currently in use, within structurally related groups of flavouring substances many do have toxicity data and this information along with knowledge of structure-activity relationships and data on the daily intake provides a framework for safety evaluation. The safety evaluation procedure provides a scientifically based practical method of integrating data on intake, structure-activity relationships, metabolism and toxicity to evaluate flavouring substances in a timely manner. The procedure has been used recently by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) to evaluate a total of 263 flavouring substances.

Correlation of structural class with no-observed-effect levels: a proposal for establishing a threshold of concern.

The relationship between chemical structure and toxicity was explored through the compilation of a large reference database consisting of over 600 chemical substances tested for a variety of endpoints resulting in over 2900 no-observed-effect levels (NOELs). Each substance in the database was classified into one of three structural classes using a decision tree approach. The resulting cumulative distributions of NOELs for each of the structural classes differed significantly from one another, supporting the contention that chemical structure defines toxicity. The database was used to derive a threshold of acceptable human exposure for each of the structural classes that could be applied in the absence of specific toxicity data on a substance within one of the three structural classes. The human exposure thresholds provide guidance on the degree of testing and evaluation required for substances that lack toxicity data.

Erythritol: an interpretive summary of biochemical, metabolic, toxicological and clinical data.

A critical and comprehensive review of the safety information on erythritol was undertaken. Numerous toxicity and metabolic studies have been conducted on erythritol in rats, mice and dogs. The toxicity studies consist of long-term feeding studies conducted to determine carcinogenic potential, intravenous and oral teratogenicity studies to determine the potential for effects on the foetus, oral studies in which erythritol was administered over one or two generations to determine the potential for reproductive effects, and studies in bacterial and mammalian systems to determine mutagenic potential. The majority of the safety studies conducted were feeding studies in which erythritol was mixed into the diet at concentrations as high as 20%. The metabolic studies in animals have shown that erythritol is almost completely absorbed, not metabolized systemically and is excreted unchanged in the urine. The safety studies have demonstrated that erythritol is well tolerated and elicits no toxicological effects. The clinical program for erythritol involved a series of single-dose and repeat-dose, short-duration studies which have been used to investigate the human correlates to the physiological responses seen in the preclinical studies. The clinical studies showed erythritol to be well tolerated and not to cause any toxicologically relevant effects, even following high-dose exposure. Erythritol administered orally to humans was rapidly absorbed from the gastrointestinal tract and quantitatively excreted in the urine without undergoing metabolic change. At high oral doses, urinary excretion accounted for approximately 90% of the administered dose with minimal amounts appearing in the faeces. A comparison of the human and animal data indicated a high degree of similarity in the metabolism of erythritol and this finding supports the use of the animal species used to evaluate the safety of erythritol for human consumption. It can be concluded, based on the available studies that erythritol did not produce evidence of toxicity.

Safety studies on products from whole coffee fruit.

The fruit of the coffee plant, Coffea arabica, has high phenolic antioxidant and phytonutrient content and could be a beneficial food ingredient. However, the fruit has historically been discarded for the favored harvesting of the coffee bean alone. CoffeeBerry products are derived from the whole fruit and include a ground whole powder, a water extract, and a more recently developed water-ethanol extract. The safety of CoffeeBerry products was evaluated in three genotoxicity studies, three short-term oral toxicity studies, and a 90-day dietary toxicity study. Bacterial mutagenicity studies and a micronucleus test using murine peripheral cells demonstrated that none of the three products showed mutagenic or genotoxic potential. In the short-term studies, despite palatability issues, female rats showed a tolerance for whole powder and ethanol extract at doses up to 8800 mg/kg bw/day. Male rats also exhibited palatability issues and tolerated lower doses of approximately 4000 mg/kg bw/day ethanol extract via gavage and approximately 2100 mg/kg bw/day whole powder or water extract in the diet. When fed in the diet to Sprague-Dawley rats for 90 days, ethanol extract showed no adverse effects at dietary concentrations of up to 5% (approximately 3446 and 4087 mg/kg bw/day for male and female rats, respectively).

Subchronic oral toxicity study of mixed tocopheryl phosphates in rats.

Rats were fed diets containing 0%, 1%, 3%, or 5% mixed tocopheryl phosphates for 90 days. No abnormal clinical signs related to treatment appeared. Some statistically significant changes in hematology and clinical chemistry parameters appeared, but the majority were not dose dependent, occurred in only one sex or group, and/or remained within the historical control range for this strain of rat. A statistically significant apparent reduction in blood protein was observed in animals treated with the tocopheryl phosphates, but further investigation showed that the test substance interfered with the protein assay. Repeat analysis using a method unaffected by plasma test substance levels showed no difference in plasma proteins among all groups. Gross necropsy revealed no abnormalities; reduced relative heart and epididymal weights were observed, but were not dose dependent and were considered incidental. Histopathological changes occurred only in the mesenteric lymph node and small intestine. Foreign material in a crystal-like form appeared in macrophages in both organs, and increased in a dose-related fashion. In the lymph node, sinus histiocytosis increased with dose, but the severity was similar between the control and low-dose groups. Foreign-body granulomatous inflammation, associated with Maltese cross birefringence of the crystals was seen in the mid- and high-dose animals, but not the low-dose group. Similarly, the small intestine showed increasing amounts of foreign material and inflammation in the mid- and high-dose but not in the 1% diet. The 1% diet (equivalent to 587 and 643 mg mixed tocopheryl phosphates/kg body weight/day for male and female rats, respectively) was considered the no observed adverse effect level.

Risk assessment of packaging materials.

Risk assessment of packaging materials provides a unique challenge. Human exposure to packaging materials and/or their components occurs from migration into foods. There are various methods for determining migration into foods. Unlike most food additives, these exposures typically are very small. Because of this, and since complete toxicological data sets are not always available for packaging materials, the US Food and Drug Administration (FDA) has developed a process to make the evaluation of packaging materials more efficient, instead of the extensive review normally required for food additives. This process is used to determine 'when the likelihood or extent of migration to food of a substance used in a food-contact article is so trivial as not to require regulation of the substance as a food additive'. This trivial level, also known as the threshold of regulation, was based upon a large database of carcinogenic potencies and was determined to be 1.5 microg/person day(-1). This was determined to 'be low enough to ensure that the public health is protected, even in the event that a substance exempted from regulation as a food additive is later found to be a carcinogen'. Substances not having structural alerts, or that are not known carcinogens or potent toxins, based on existing toxicological information, and are below the threshold value, are considered by the FDA to be exempted from regulation as food additives. The threshold of regulation approach used by the FDA provides an excellent model by which to evaluate the majority of packaging materials.