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

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Abstract

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.

Highlights

► Aliphatic and aromatic terpene hydrocarbons used as flavor ingredients and resultant exposure are reported. ► Review of absorption, distribution, metabolism and elimination of terpene hydrocarbons. ► Review of short- and long-term toxicology and reproductive toxicology of terpene hydrocarbons. ► Discussion of effects in bioassays and the relevance to humans. ► Review of genotoxicity data on aliphatic and aromatic terpene hydrocarbons.

Introduction

Aliphatic and terpene hydrocarbons are ubiquitous through the food chain, therefore it is not surprising that they serve as effective flavoring ingredients. They are often used to convey citrus, pine, balsamic, woody and fruity notes. Consumers are exposed to aliphatic and terpene hydrocarbons from a variety of ingested and environmental sources (Helmig et al., 1999a, Helmig et al., 1999b, Guenther et al., 2000). The volume of use as flavor ingredients for aliphatic and aromatic terpene hydrocarbons prompted the FEMA Expert Panel to conduct this review of the relevant literature in support of the safe use of this group in food.

Section snippets

Chemical identity

This summary presents the key scientific data relevant to the safety evaluation of 17 aliphatic and aromatic terpene hydrocarbons used as flavoring ingredients. All substances in the group are unsaturated and include (1) three branched-chain aliphatic hydrocarbons and one structurally related unsaturated linear hydrocarbon, (2) six alkyl-substituted alicyclic and six bicyclic hydrocarbons, and (3) one alkyl-substituted aromatic hydrocarbon (Table 1).

Flavor use, natural occurrence in food, and exposure

The total annual volume of the 17 flavoring ingredients in this group is approximately 249,000 kg in the USA (Gavin and Williams, 2008). Greater than 99.9% of the total volume in the USA is accounted for by naturally occurring acyclic (e.g., myrcene), monocyclic (e.g., limonene), bicyclic (e.g., α-pinene), and monoaromatic (e.g., p-cymene) terpene hydrocarbons. The per capita intake

Acyclic branched-chain hydrocarbons

Greater than 70% of an oral dose of 400–700 mg/kg bw of myrcene given daily for 2 days to male albino rabbits was excreted in the urine as diol metabolites collected over 3 days (Ishida et al., 1981). The same metabolites were observed in the urine of adult male IISC rats given 800 mg/kg bw of myrcene daily by oral intubation for 20 days (Madyastha and Srivatsan, 1987).

Monocyclic hydrocarbons

Monocyclic hydrocarbons, such as d-limonene, administered orally are rapidly absorbed and distributed throughout the body. Following

Acute toxicity

Oral LD50 values have been reported for 16 of the 17 substances in this group (see Table 2). LD50 values range from 1590 to greater than 8000 mg/kg bw in rats, and 2000 to greater than 13,360 mg/kg bw in mice. These values indicate that aliphatic and aromatic hydrocarbons exhibit low acute oral toxicity (Brownlee, 1940, Clark et al., 1979, Dogra et al., 1989, Hart and Wong, 1971, Hasegawa et al., 1989, Jenner et al., 1964, Keating, 1972, Levenstein, 1975, Moreno, 1972a, Moreno, 1972b, Moreno, 1972c

Conclusions

Upon evaluation of the scientific data relevant to the safety evaluation of the use of aliphatic and aromatic terpene hydrocarbons as flavoring ingredients, it was concluded that they present no safety issues to humans. Although members of this group have been shown to exhibit renal carcinogenic potential in the male F344N/rat, the mechanism leading to these findings is known and strongly indicates that the nephropathy associated with monoterpene hydrocarbons have no significance for human risk

Conflict of Interest

The authors declare that there are no conflicts of interest.

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