The FEMA GRAS assessment of aliphatic and aromatic terpene hydrocarbons used as flavor ingredients.

This publication is the thirteenth in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. Since then, the number of flavoring substances has grown to more than 2600 substances. 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 and aromatic terpene hydrocarbons as flavoring ingredients are evaluated. The group of aliphatic and aromatic terpene hydrocarbons was reaffirmed as GRAS (GRASr) based, in part, on their self-limiting properties as flavoring substances in food; 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 and chronic studies and the lack of significant genotoxic potential.

The FEMA GRAS assessment of alpha,beta-unsaturated aldehydes and related substances used as flavor ingredients.

This publication is the 12th in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. Since then, the number of flavoring substances has grown to more than 2200 chemically-defined substances. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, toxicodynamics and toxicology. Scientific data relevant to the safety evaluation for the use of aliphatic, linear alpha,beta-unsaturated aldehydes and structurally related substances as flavoring ingredients are evaluated. The group of substances was reaffirmed as GRAS (GRASr) based, in part, on their self-limiting properties as flavoring substances in food; their low level of flavor use; the rapid absorption and metabolism of low in vivo concentrations by well-recognized biochemical pathways; adequate metabolic detoxication at much higher levels of exposure in humans and animals; the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels determined from subchronic and chronic studies. While some of the compounds described here have exhibited positive in vitro genotoxicity results, evidence of in vivo genotoxicity and carcinogenicity occurs only under conditions in which animals are repeatedly and directly exposed to high irritating concentrations of the aldehyde. These conditions are not relevant to humans who consume alpha,beta-unsaturated aldehydes as flavor ingredients at low concentrations distributed in a food or beverage matrix.

Aspartame: a safety evaluation based on current use levels, regulations, and toxicological and epidemiological studies.

Aspartame is a methyl ester of a dipeptide used as a synthetic nonnutritive sweetener in over 90 countries worldwide in over 6000 products. The purpose of this investigation was to review the scientific literature on the absorption and metabolism, the current consumption levels worldwide, the toxicology, and recent epidemiological studies on aspartame. Current use levels of aspartame, even by high users in special subgroups, remains well below the U.S. Food and Drug Administration and European Food Safety Authority established acceptable daily intake levels of 50 and 40 mg/kg bw/day, respectively. Consumption of large doses of aspartame in a single bolus dose will have an effect on some biochemical parameters, including plasma amino acid levels and brain neurotransmitter levels. The rise in plasma levels of phenylalanine and aspartic acid following administration of aspartame at doses less than or equal to 50 mg/kg bw do not exceed those observed postprandially. Acute, subacute and chronic toxicity studies with aspartame, and its decomposition products, conducted in mice, rats, hamsters and dogs have consistently found no adverse effect of aspartame with doses up to at least 4000 mg/kg bw/day. Critical review of all carcinogenicity studies conducted on aspartame found no credible evidence that aspartame is carcinogenic. The data from the extensive investigations into the possibility of neurotoxic effects of aspartame, in general, do not support the hypothesis that aspartame in the human diet will affect nervous system function, learning or behavior. Epidemiological studies on aspartame include several case-control studies and one well-conducted prospective epidemiological study with a large cohort, in which the consumption of aspartame was measured. The studies provide no evidence to support an association between aspartame and cancer in any tissue. The weight of existing evidence is that aspartame is safe at current levels of consumption as a nonnutritive sweetener.

The FEMA GRAS assessment of aromatic substituted secondary alcohols, ketones, and related esters used as flavor ingredients.

This publication is the 11th in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. The list of GRAS substances has now grown to more than 2100 substances. 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. In this monograph, a detailed interpretation is presented on the renal carcinogenic potential of the aromatic secondary alcohol alpha-methylbenzyl alcohol, aromatic ketone benzophenone, and corresponding alcohol benzhydrol. The relevance of these effects to the flavor use of these substances is also discussed. The group of aromatic substituted secondary alcohols, ketones, and related esters was reaffirmed as GRAS (GRASr) 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 and chronic studies and the lack of significant genotoxic and mutagenic potential.

Critique of dose response in carcinogenesis.

A few landmarks in the development of dose response in toxicology are presented, with an explanation of why dose should only be considered on a logarithmic scale. Examples are shown, illustrating that the current practice of labeling dose-response curves for carcinogenesis as supralinear, linear or sublinear, is meaningless unless the dose-response scales are defined. Since many reports labeling such curves as supralinear, linear, or sublinear are carried out with dose on a linear scale, the scientific significance of the shape of the curve is obscured. Examples of dose-response curves for carcinogenesis from 2-acetylaminofluorene, N-nitrosodiethylamine, aflatoxins, and radium are shown. In addition, more than 500 National Toxicology Program Technical Reports (NTP-TR) on carcinogenicity were examined; from this database, three groups of studies were selected. The first group consisted of those studies in which the lowest dose produced no tumors and the study had a positive dose response. The second group consisted of those studies with three or more doses, with a positive dose response producing tumors, but in which there were no tumors in the control group. The third group of more than 50 studies was from NTP-TR-00 to NTP-TR-52 that had only two data points with a positive dose response. These studies were all evaluated on the Rozman et al. scale, since it conforms to the laws of nature and allows evaluation of all doses. It was observed that virtually all of these NTP-TR carcinogenicity studies show a linear response when dose is on this logarithmic scale; a clear threshold for carcinogenicity is typical for nearly all of these chemicals. An exponential dose-response curve was a better fit for a few, but experimental error could account for this deviation from linearity. It is pointed out that there is strong experimental evidence that the mere presence of DNA adducts does not necessarily lead to tumor production. Hormesis probably applies to carcinogenesis and proof of this will require abandoning the no threshold concept. Experiments showing that cumulative dose is a better metric than daily dose may require reevaluating almost all carcinogenicity studies.

The FEMA GRAS assessment of phenethyl alcohol, aldehyde, acid, and related acetals and esters used as flavor ingredients.

This publication is the ninth in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. 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 phenethyl alcohol, aldehyde, acid, and related acetals and esters as flavoring ingredients is evaluated. The group of phenethylalcohol, aldehyde, acid, and related acetals and esters was reaffirmed as GRAS (GRASr) based, in part, on their self-limiting properties as flavoring substances in food, 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 and chronic studies and the lack of significant genotoxic and mutagenic potential. This evidence of safety is supported by the fact that the intake of phenethyl alcohol, aldehyde, acid, and related acetals and esters as natural components of traditional foods is greater than their intake as intentionally added flavoring substances.

The FEMA GRAS assessment of benzyl derivatives used as flavor ingredients.

This publication is the eighth in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. 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 benzyl derivatives as flavoring ingredients is evaluated. The group of benzyl derivatives was reaffirmed as GRAS (GRASr) based, in part, on their self-limiting properties as flavoring substances in food; 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 and chronic studies and the lack of significant genotoxic and mutagenic potential. This evidence of safety is supported by the fact that the intake of benzyl derivatives as natural components of traditional foods is greater than their intake as intentionally added flavoring substances.

The FEMA GRAS assessment of hydroxy- and alkoxy-substituted benzyl derivatives used as flavor ingredients.

This publication is the ninth in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. 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 hydroxy- and alkoxy-substituted benzyl derivatives as flavoring ingredients is evaluated. The group of hydroxy- and alkoxy-benzyl derivatives was reaffirmed as GRAS (GRASr) based, in part, on their self-limiting properties as flavoring substances in food; 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 and chronic studies and the lack of significant genotoxic and mutagenic potential. This evidence of safety is supported by the fact that the intake of hydroxy- and alkoxy-substituted benzyl derivatives as natural components of traditional foods is greater than their intake as intentionally added flavoring substances.

A procedure for the safety evaluation of natural flavor complexes used as ingredients in food: essential oils.

A scientifically based guide has been developed to evaluate the safety of naturally occurring mixtures, particularly essential oils, for their intended use as flavor ingredients. The approach relies on the complete chemical characterization of the essential oil and the variability of the composition of the oil in the product intended for commerce. Being products of common plant biochemical pathways, the chemically identified constituents are organized according to a limited number of well-established chemical groups called congeneric groups. The safety of the intake of the each congeneric group from consumption of the essential oil is evaluated in the context of data on absorption, metabolism, and toxicology of members of the congeneric group. The intake of the group of unidentified constituents is evaluated in the context of the consumption of the essential oil as a food, a highly conservative toxicologic threshold, and toxicity data on the essential oil or an essential oil of similar chemotaxonomy. The flexibility of the guide is reflected in the fact that high intake of major congeneric groups of low toxicologic concern will be evaluated along with low intake of minor congeneric groups of significant toxicological concern (i.e., higher structural class). The guide also provides a comprehensive evaluation of all congeneric groups and constituents that account for the majority of the composition of the essential oil. The overall objective of the guide is to organize and prioritize the chemical constituents of an essential oil in order that no reasonably possible significant risk associated with the intake of essential oil goes unevaluated. The guide is, however, not intended to be a rigid checklist. The Flavor and Extract Manufacturers Association (FEMA) Expert Panel will continue to evaluate each essential oil on a case by case basis applying their scientific judgment to insure that each natural flavor complex is exhaustively evaluated.

Safety evaluation of natural flavour complexes.

Natural flavour complexes (NFCs) are chemical mixtures obtained by applying physical separation methods to botanical sources. Many NFCs are derived from foods. In the present paper, a 12-step procedure for the safety evaluation of NFCs, 'the naturals paradigm', is discussed. This procedure, which is not intended to be viewed as a rigid check list, begins with a description of the chemical composition of the commercial product, followed by a review of the data on the history of dietary use. Next, each constituent of an NFC is assigned to one of 33 congeneric groups of structurally related substances and to one of three classes of toxic potential, each with its own exposure threshold of toxicological concern. The group of substances of unknown structure is placed in the class of greatest toxic potential. In subsequent steps, for each congeneric group the procedure determines the per capita intake, considers metabolic pathways and explores the need and availability of toxicological data. Additional toxicological and analytical data may be required for a comprehensive safety evaluation. The procedure concludes with an evaluation of the NFC in its entirety, also considering combined exposure to congeneric groups. The first experiences with the use of this procedure are very promising. Future safety evaluations of larger numbers of NFCs will indicate the usefulness of the system, either in its present form or in a form modified on the basis of experience.

Threshold for carcinogenicity of N-nitrosodiethylamine for esophageal tumors in rats.

In a study on 4080 rats by Peto et al. [Cancer Res. 51 (1991) 6415], esophageal neoplasms induced by N-nitrosodiethylamine (NDEA) were the tumors most clearly demonstrated to have a dose response from administration of the compound to male rats. However, they were unable to predict the shape of the dose-response curve at low doses. These data were reanalyzed in the present study for dose response on a logarithmic scale for dose. In contrast to the conclusion of Peto et al., the reanalysis shows a convincingly sharp threshold at 10(17.1) molecules/kg/day. This unequivocal threshold has substantial implications for risk assessment of chemical carcinogens.

Safety assessment of allylalkoxybenzene derivatives used as flavouring substances - methyl eugenol and estragole.

This publication is the seventh in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers' Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavouring substances under conditions of intended use. In this review, scientific data relevant to the safety evaluation of the allylalkoxybenzene derivatives methyl eugenol and estragole is critically evaluated by the FEMA Expert Panel. The hazard determination uses a mechanism-based approach in which production of the hepatotoxic sulfate conjugate of the 1'-hydroxy metabolite is used to interpret the pathological changes observed in different species of laboratory rodents in chronic and subchronic studies. In the risk evaluation, the effect of dose and metabolic activation on the production of the 1'-hydroxy metabolite in humans and laboratory animals is compared to assess the risk to humans from use of methyl eugenol and estragole as naturally occurring components of a traditional diet and as added flavouring substances. Both the qualitative and quantitative aspects of the molecular disposition of methyl eugenol and estragole and their associated toxicological sequelae have been relatively well defined from mammalian studies. Several studies have clearly established that the profiles of metabolism, metabolic activation, and covalent binding are dose dependent and that the relative importance diminishes markedly at low levels of exposure (i.e. these events are not linear with respect to dose). In particular, rodent studies show that these events are minimal probably in the dose range of 1-10 mg/kg body weight, which is approximately 100-1000 times the anticipated human exposure to these substances. For these reasons it is concluded that present exposure to methyl eugenol and estragole resulting from consumption of food, mainly spices and added as such, does not pose a significant cancer risk. Nevertheless, further studies are needed to define both the nature and implications of the dose-response curve in rats at low levels of exposure to methyl eugenol and estragole.

The FEMA GRAS assessment of pyrazine derivatives used as flavor ingredients. Flavor and Extract Manufacturers Association.

This is the fifth in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics and toxicology. Flavor ingredients are evaluated individually taking into account the available scientific information on the group of structurally related substances. Scientific data relevant to the safety evaluation of the use of pyrazine derivatives as flavoring ingredients is evaluated.

Toxicologic considerations in the diagnosis of occupational asthma.

BACKGROUND: The consideration of dose for chemicals inducing occupational asthma is examined from the point of view of a toxicologist. Two widely used chemicals in industry, toluene diisocyanate (TDI) and formaldehyde, are used as examples of agents that are formally recognized by OSHA to cause occupational asthma. The Permissible Exposure Limit (PEL) of OSHA and the Threshold Limit Value (TLV) of ACGIH for TDI are identical and are in the range of values for which occupational asthma has been reported in some workers. The narrow range of exposure values for TDI in studies of workers with and without asthma is discussed and correlated with the background concentration of TDI in the ambient atmosphere. For formaldehyde, the PEL and TLV, in contrast, offer a wide margin of safety for the inducement of occupational asthma. CONCLUSION: From this disparity in exposure limits for TDI and formaldehyde, it is concluded that occupational exposure limits by agencies for specific chemicals do not provide a reliable indication of the concentration of a chemical that is necessary to produce occupational asthma. The need for a better appreciation of dose response, particularly relative to background, ambient levels, in the evaluation of occupational asthma is emphasized.

Uptake, disposition, and persistence of acrylonitrile in rainbow trout.

The uptake and disposition of [2,3-14C]acrylonitrile-derived 14C were studied in rainbow trout by water exposure. Trout were exposed to [14C]ACN at 5.3 micrograms/liter and sampled at various times during a 24-hr uptake phase. After transfer to fresh water, fish were sampled to 72 hr for the estimation of elimination rates and the half-life of 14C. Throughout these experiments several fish were also sacrificed for whole-body autoradiography. The uptake of 14C in carcass and viscera began to level off at 24 hr and the apparent elimination studies, the 14C appeared to persist in both muscle and octanol-water partition coefficient (log p = -0.92). The t1/2 of 14C in muscle in two such experiments was calculated to be 117 and 102 hr. The autoradiographs of whole-body sections of exposed trout also revealed a slow loss of 14C from muscle. Muscle extracts prepared from exposed fish were essentially nondialyzable. When dialyzed muscle extract was analyzed for protein and 14C after SDS-PAGE electrophoresis, most of the 14C was associated with a single protein band with a mobility comparable to standards in the 10,000 Dalton range. These studies indicate that the long halflife of 14C seen in trout muscle may be due to covalent binding of 14C to a protein with a molecular weight of approximately 10,000 Daltons.

The science of toxicology and its relevance to MCS.

The definitions and current practice of multiple chemical sensitivity (MCS) are considered in relation to the fundamental principles of toxicology. The salient problem with MCS is that there is no consistent and specific effect from exposure to any specific chemical. This does not allow for any objective test for any disease entity which might be caused by the chemicals as indicated by the theory of MCS. The effects of exposure to chemicals as defined today as MCS are subjective and no report is available to convincingly demonstrate that these effects would not have occurred merely by chance. It is concluded that (1) MCS, as defined, does not allow specificity or consistency for biological reactions to the effects of chemicals; (2) MCS does not provide a testable hypothesis; (3) MCS is contradictory to the fundamental principles of toxicology; (4) current testing procedures for MCS are so subjective that they are useless; (5) there is no evidence that the responses attributed to MCS are any other than those that would occur merely by chance; and (6) the MCS literature attaches an emotional bias to chemicals.