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In the event that insufficient data are available to evaluate a congeneric group at Step 7, or the currently available data result in margins of safety that are not sufficient, the essential oil cannot be further evaluated by this guide and must be set aside for further considerations.

Use of the guide requires scientific judgment at each step of the sequence. For instance, if a congeneric group that accounted for 20% of a high-volume essential oil was previously evaluated and found to be safe under intended conditions of use, the same congeneric group found at less than 2% of a low-volume essential oil does not need to be further evaluated.

Step 8 considers additivity or synergistic interactions between individual substances and between the different congeneric groups in the essential oil. As for all other toxicological concerns, the level of exposure to congeneric groups is relevant to whether additive or synergistic effects present a significant health hazard. The vast majority of essential oils are used in food in extremely low concentrations, which therefore results in very low intake levels of the different congeneric groups within that oil. Moreover, major representative constituents of each congeneric group have been tested individually and pose no toxicological threat even at dose levels that are orders of magnitude greater than normal levels of intake of essential oils from use in traditional foods. Based on the results of toxicity studies both on major constituents of different congeneric groups in the essential oil and on the essential oil itself, it can be concluded that the toxic potential of these major constituents is representative of that of the oil itself, indicating the likely absence of additivity and synergistic interaction. In general, the margin of safety is so wide and the possibility of additivity or synergistic interaction so remote that combined exposure to the different congeneric groups and the unknowns are considered of no health concern, even if expert judgment cannot fully rule out additivity or synergism. However, case-by-case considerations are appropriate. Where possible combined effects might be considered to have toxico-logical relevance, additional data may be needed for an adequate safety evaluation of the essential oil.

Additivity of toxicologic effect or synergistic interaction is a conservative default assumption that may be applied whenever the available metabolic data do not clearly suggest otherwise. The extensive database of metabolic information on congeneric groups (JECFA, 1997-2004) that are found in essential oils suggests that the potential for additive effects and synergistic interactions among congeneric groups in essential oils is extremely low. Although additivity of effect is the approach recommended by National Academy of Sciences (NAS)/National Research Council (NRC) committees (NRC, 1988, 1994) and regulatory agencies (EPA, 1988), the Presidential Commission of Risk Assessment and Risk Management recommended (Presidential Commission, 1996, p. 68) that "For risk assessments involving multiple chemical exposures at low concentrations, without information on mechanisms, risks should be added. If the chemicals act through separate mechanisms, their attendant risks should not be added but should be considered separately." Thus, the risks of chemicals that act through different mechanisms, that act on different target systems, or that are toxicologically dissimilar in some other way should be considered to be independent of each other. The congeneric groups in essential oils are therefore considered separately.

Further, the majority of individual constituents that comprise essential oils are themselves used as flavoring substances that pose no toxicological threat at doses that are magnitudes greater than their level of intake from the essential oil. Rulis (1987) reported that "The overwhelming majority of additives present a high likelihood of having safety assurance margins in excess of 105." He points out that this is particularly true for additives used in the USA at less than 100,000 lb/yr. Because more than 90% of all flavoring ingredients are used at <10,000 lb/yr (Hall and Oser, 1968), this alone implies intakes commonly many orders of magnitude below the no-effect level. Nonadditivity thus can often be assumed. As is customary in the evaluation of any substance, high-end data for exposure (consumption) are used, and multiple other conservatisms are employed to guard against underestimation of possible risk. All of these apply to complex mixtures as well as to individual substances.

7.5.2.3.1 Cornmint Oil Congeneric Groups

In cornmint oil, the principal congeneric group is composed of terpene alicyclic secondary alcohols, ketones, and related esters, as represented by the presence of (-)-menthol, (-)-menthone,

(+)-isomenthone, (-)-menthyl acetate, and other related substances. Samples of triple-distilled commercial cornmint oil may contain up to 95% of this congeneric group. The biochemical and biological fate of this group of substances has been previously reviewed (Adams et al., 1996; JECFA, 1999). Key data on metabolism, toxicity, and carcinogenicity are cited below in order to complete the evaluation. Although constituents in this group are effectively detoxicated via conjugation of the corresponding alcohol or w-oxidation followed by conjugation and excretion (Yamaguchi et al., 1994; Madyastha and Srivatsan, 1988; Williams, 1940), the intake of the congeneric group (3044 pg/person/d or 3.04 mg/person/d; see Table 7.2) is higher than the exposure threshold of 540 pg/person/d or 0.540 mg/person/d for Structural Class II. Therefore, toxicity data are required for this congeneric group. In both short- and long-term studies (Madsen et al., 1986; JEFCA, 2000a), menthol, menthone, and other members of the group exhibit no-observable-adverse-effect-levels (NOAELs) at least 1000 times the daily PCI ("eaters only") (3.04 mg/person/d or 0.05 mg/kg bw/d) of this congeneric group resulting from intake of the essential oil. For members of this group, numerous in vitro and in vivo genotoxicity assays are consistently negative (Heck et al., 1989; Sasaki et al., 1989; Muller, 1993; Florin et al., 1980; Rivedal et al., 2000; Zamith et al., 1993; NTP Draft, 2003). Therefore, the intake of this congeneric group from consumption of Mentha arvensis is not a safety concern.

Although it is a constituent of cornmint oil and is also a terpene alicyclic ketone structurally related to the above congeneric group, pulegone exhibits a unique structure (i.e., 2-isopropy-lidenecyclohexanone) that participates in a well-recognized intoxication pathway (Figure 7.2) (McClanahan et al., 1989; Thomassen et al., 1992; Adams et al., 1996; Chen et al., 2001) that leads to the formation of menthofuran. This metabolite subsequently oxidizes and the ring opens to yield a highly reactive 2-ene-1,4-dicarbonyl intermediate that reacts readily with proteins resulting in hepatotoxicity at intake levels at least two orders of magnitude less than no observable effect levels for structurally related alicyclic ketones and secondary alcohols (menthone, carvone, and menthol). Therefore, pulegone and its metabolite (menthofuran), which account for <2% of commercial cornmint oil, are considered separately in the guide. In this case, the daily PCI of 64 pg/person/d (1.07 pg/kg bw/d) does not exceed the 90 pg/d threshold for Class III. However, a 90-day study on pulegone (NTP, 2002) showed a NOAEL (9.375 mg/kg bw/d) that is approximately 8700 times the intake of pulegone and its metabolites as constituents of cornmint oil. Also, in a 28-day study with peppermint oil (Mentha piperita) containing approximately 4% pulegone and menthofuran, a NOAEL of 200 mg/kg bw/d for male rats and a NOAEL of 400 mg/kg bw/d for female rats were established that corresponds to a NOAEL of 8 mg/kg bw/d for pulegone and menthofuran (Serota, 1990). In a 90-day study with a mixture of Mentha piperita and Mentha arvensis oils (Splindler and Madsen, 1992; Smith et al., 1996), a NOAEL of 100 mg/kg bw/d was established that corresponds to a NOAEL of 4 mg/kg bw/d for pulegone and menthofuran.

The only other congeneric group that accounts for >2% of the composition of cornmint oil is a congeneric group of terpene hydrocarbons [(+) and (-)-pinene, (+) limonene, etc.]. Although these may contribute up to 8% of the oil, upon multiple redistillations during processing the hydrocarbon content can be significantly reduced (<3%) in the finished commercial oil. Using the 8% figure to determine a conservative estimate of intake, the intake of terpene hydrocarbons is 256 pg/person/d (4.27 pg/kg bw/d). This group is predominantly metabolized by cytochrome P450-catalyzed hydrox-ylation, conjugation, and excretion (Ishida et al., 1981; Madyastha and Srivatsan, 1987; Crowell et al., 1994; Poon et al., 1996; Vigushin et al., 1998; Miyazawa et al., 2002). The daily PCI of 256 pg/person/d is less than the exposure threshold (1800 pg/person/d) for Structural Class I. Although no additional data would be required to complete the evaluation of this group, NOAELs (300 mg/kg bw/d) from long-term studies (NTP, 1990) on principal members of this group are orders of magnitude greater than the daily PCI ("eaters only") of terpene hydrocarbons (0.025 mg/kg bw/d). Therefore, all congeneric groups in cornmint oil are considered safe for use when consumed in cornmint oil.

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