Maria Bastaki

Impact of structural and metabolic variations on the toxicity and carcinogenicity of hydroxy- and alkoxy-substituted allyl- and propenylbenzenes

The metabolic fate of a compound is determined by numerous factors including its chemical structure. Although the metabolic options for a variety of functional groups are well understood and can often provide a rationale for the comparison of toxicity based on structural analogy, at times quite minor structural variations may have major consequences for metabolic outcomes and toxicity. In this perspective, the effects of structural variations on metabolic outcomes is detailed for a group of related hydroxy- and alkoxy-substituted allyl- and propenylbenzenes. These classes of compounds are naturally occurring constituents of a variety of botanical-based food items. The classes vary from one another by the presence or absence of alkylation of their para-hydroxyl substituents and/or the position of the double bond in the alkyl side chain. We provide an overview of how these subtle structural variations alter the metabolism of these important food-borne compounds, ultimately influencing their toxicity, particularly their DNA reactivity and carcinogenic potential. The data reveal that detailed knowledge of the consequences of subtle structural variations for metabolism is essential for adequate comparison of structurally related chemicals. Taken together, it is concluded that predictions in toxicological risk assessment should not be performed on the basis of structural analogy only but should include an analogy of metabolic pathways across compounds and species.

Safety evaluation of substituted thiophenes used as flavoring ingredients

This publication is the second in a series by the Expert Panel of the Flavor and Extract Manufacturers Association summarizing the conclusions of its third systematic re-evaluation of the safety of flavorings previously considered to be generally recognized as safe (GRAS) under conditions of intended use. Re-evaluation of GRAS status for flavorings is based on updated considerations of exposure, structural analogy, metabolism, pharmacokinetics and toxicology and includes a comprehensive review of the scientific information on the flavorings and structurally related substances. Of the 12 substituted thiophenes reviewed here, 11 were reaffirmed as GRAS based on their rapid absorption, metabolism and excretion in humans and animals; the low estimated dietary exposure from flavor use; the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels; and the lack of significant genotoxic and mutagenic potential. For one of the substituted thiophenes, 3-acetyl-2,5-dimethylthiophene, it was concluded that more detailed exposure information, comparative metabolism studies and comprehensive toxicity data, including an in-depth evaluation of the mechanism of action for any adverse effects observed, are required for continuation of its FEMA GRAS™ status. In the absence of these data, the compound was removed from the FEMA GRAS list.

GRASr2 Evaluation of Aliphatic Acyclic and Alicyclic Terpenoid Tertiary Alcohols and Structurally Related Substances Used as Flavoring Ingredients

This publication is the 1st in a series of publications by the Expert Panel of the Flavor and Extract Manufacturers Assoc. summarizing the Panels 3rd re-evaluation of Generally Recognized as Safe (GRAS) status referred to as the GRASr2 program. In 2011, the Panel initiated a comprehensive program to re-evaluate the safety of more than 2700 flavor ingredients that have previously met the criteria for GRAS status under conditions of intended use as flavor ingredients. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics, and toxicology. Flavor ingredients are evaluated individually and in the context of the available scientific information on the group of structurally related substances. Scientific data relevant to the safety evaluation of the use of aliphatic acyclic and alicyclic terpenoid tertiary alcohols and structurally related substances as flavoring ingredients are evaluated. The group of aliphatic acyclic and alicyclic terpenoid tertiary alcohols and structurally related substances was reaffirmed as GRAS (GRASr2) based, in part, on their rapid absorption, metabolic detoxication, and excretion in humans and other animals; their low level of flavor use; the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels determined from subchronic studies and the lack of significant genotoxic and mutagenic potential.

The safety evaluation of food flavouring substances: the role of metabolic studies

The safety assessment of a flavour substance examines several factors, including metabolic and physiological disposition data. The present article provides an overview of the metabolism and disposition of flavour substances by identifying general applicable principles of metabolism to illustrate how information on metabolic fate is taken into account in their safety evaluation. The metabolism of the majority of flavour substances involves a series both of enzymatic and non-enzymatic biotransformation that often results in products that are more hydrophilic and more readily excretable than their precursors. Flavours can undergo metabolic reactions, such as oxidation, reduction, or hydrolysis that alter a functional group relative to the parent compound. The altered functional group may serve as a reaction site for a subsequent metabolic transformation. Metabolic intermediates undergo conjugation with an endogenous agent such as glucuronic acid, sulphate, glutathione, amino acids, or acetate. Such conjugates are typically readily excreted through the kidneys and liver. This paper summarizes the types of metabolic reactions that have been documented for flavour substances that are added to the human food chain, the methodologies available for metabolic studies, and the factors that affect the metabolic fate of a flavour substance.

Absence of renal adverse effects from β-myrcene dietary administration in OECD guideline-compliant subchronic toxicity study

β-Myrcene is a flavoring substance that occurs naturally in a large variety of foods. At the request of the European Food Safety Authority (EFSA) for additional toxicological data on β-myrcene, groups of Sprague Dawley rats (10/sex/group) were administered diets containing 0, 700, 2100, or 4200 ppm of β-myrcene designed to provide nominal doses of 0, 50, 150, or 300 mg/kg bw/day in a 90-day GLP-compliant study. Based on body weights, feed consumption, and substance stability data, final estimated daily intakes of β-myrcene were calculated to be 20.4, 58.8, and 115.2 mg/kg bw for males and 24.2, 70.0, and 135.9 mg/kg bw for females. No effects on clinical observations, hematology and clinical chemistry parameters, organ weights, or macroscopic and histopathological examinations were found attributable to ingestion of β-myrcene. The oral no-observed-adverse-effect level (NOAEL) for rats of both sexes was the highest dose tested. Based on feed consumption and test substance stability in the diet, the NOAEL was calculated to be 115 and 136 mg/kg bw/day for males and females, respectively.

Absence of adverse effects following administration of piperine in the diet of Sprague-Dawley rats for 90 days

Piperine (E,E-) is a naturally occurring pungent and spicy constituent of black pepperand is also used as an added flavoring ingredient to foods and beverages. Piperine has been determined safe under conditions of intended use as a flavoring substance by regulatory and scientific expert bodies. While concurring with the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and Flavor and Extract Manufacturers Association (FEMA) Expert Panel on the safety of piperine, the European Food Safety Authority (EFSA) requested additional toxicological data. The results of a 90-day GLPcompliant dietary study, conducted in Sprague-Dawley rats at target doses of 0, 5, 15, or 50 mg/kg bw/day, to respond to this request are presented herein. No adverse effects were found attributable to ingestion of piperine. Statistically significant changes in food consumption, body weight gain, and plasma cholesterol levels were not considered adverse as discussed in this paper. Therefore, the oral no-observed-adverse-effect level (NOAEL) was determined to be the highest dose tested of 50 mg/kg bw/day. EFSA derived a lower NOAEL of 5 mg/kg bw/day based on increased plasma cholesterol levels which still affords an adequate margin of safety of over 48,000 and concluded that piperine is not of safety concern.

Absence of adverse effects following the gavage administration of methyl propyl trisulfide to Sprague-Dawley rats for 90 days

Methyl propyl trisulfide is a flavoring substance found in foods such as garlic and onions. At the request of the European Food Safety Authority (EFSA) for additional toxicological data on methyl propyl trisulfide, groups of Sprague-Dawley rats (10/sex/group) were gavaged with 0 (corn oil vehicle control), 0.5, 2, or 6 mg methyl propyl trisulfide/kg bw/day in a 90-day GLP-compliant study. No effects on clinical observations, hematology and clinical chemistry parameters, organ weights, or macroscopic and histopathological examinations were found attributable to ingestion of methyl propyl trisulfide. The oral no-observed-adverse-effect level (NOAEL) for rats of both sexes was the highest dose tested of 6 mg/kg bw/day.

Estimated daily intake and safety of FD&C food-colour additives in the US population

ABSTRACT A refined exposure assessment was undertaken to calculate the estimated daily intake (EDI) of the seven FD&C straight-colour additives and five FD&C colour lakes (‘synthetic’ food colours) approved in the United States. The EDIs were calculated for the US population as a whole and specific age groups, including children aged 2–5 and 6–12 years, adolescents aged 13–18 years, and adults aged 19 or more y. Actual use data were collected from an industry survey of companies that are users of these colour additives in a variety of products, with additional input from food colour manufacturers. Food-consumption data were obtained from the National Health and Nutrition Examination Survey (NHANES). The assessment was further refined by adjusting the intake to more realistic scenarios based on the fraction of products containing colour within specific food categories using data provided by the Mintel International Group Ltd. The results of the analysis indicate that (1) the use levels reported by the industry are consistent with the concentrations measured analytically by the US Food and Drug Administration; and (2) exposure to food-colour additives in the United States by average and high-intake consumers is well below the acceptable daily intake (ADI) of each colour additive as published by the Joint WHO/FAO Committee on Food Additives (JECFA) and allows wide margins of safety. It is concluded that food colour use as currently practised in the United States is safe and does not result in excessive exposure to the population, even at conservative ranges of food consumption and levels of use.