The guide does not employ criteria commonly used for the safety evaluation of individual chemical substances. Instead, it is a procedure involving a comprehensive evaluation of the chemical and biological properties of the constituents and congeneric groups of an essential oil. Constituents in the oil that are of known structure are organized into congeneric groups that exhibit similar metabolic and toxicologic properties. The congeneric groups are further classified according to levels (Structural Classes I, II, and III) of toxicologic concern using a decision-tree approach (Cramer et al., 1978; Munro et al., 1996). Based on intake data for the essential oil and constituent concentrations, the congeneric groups are prioritized according to intake and toxicity potential. The procedure ultimately focuses on those congeneric groups that due to their structural features and intake may pose some significant risk from the consumption of the essential oil. Key elements used to evaluate congeneric groups include exposure, structural analogy, metabolism, and toxicology, which include toxicity, carcinogenicity, and genotoxic potential (Adams et al., 1996, 1997, 1998, 2004; Woods and Doull, 1991; Oser and Ford, 1991; Oser and Hall, 1977; Newberne et al., 1999; Smith et al., 2002a, 2002b). Throughout the analysis of these data, it is essential that professional judgment and expertise be applied to complete the safety evaluation of the essential oil. As an example of how a typical evaluation process for an essential oil is carried out according to this guide, the safety evaluation for flavor use of cornmint oil (Mentha arvensis) is outlined in Section 184.108.40.206.1.
7.5.2 Elements of the Guide for the Safety Evaluation of the Essential Oil
In Step 1 of the guide, the evaluation procedure estimates intake based on industry survey data for each essential oil. It then organizes the chemically identified constituents that have an intake >1.5 pg/d into congeneric groups that participate in common pathways of metabolism and exhibit similar toxic potential. In Steps 2 and 3, each identified chemical constituent is broadly classified according to toxic potential (Cramer et al., 1978) and then assigned to a congeneric group of structurally related substances that exhibit similar pathways of metabolism and toxicologic potential.
Before the formal evaluation begins, it is necessary to specify the data (e.g., botanical, physical, and chemical) required to completely describe the product being evaluated. In order to effectively evaluate an essential oil, attempted complete analyses must be available for the product intended for the marketplace from a number of flavor manufacturers. Additional quality control data are useful, as they demonstrate consistency in the chemical composition of the product being marketed. A Technical Information paper drafted for the particular essential oil under consideration organizes and prioritizes these data for efficient sequential evaluation of the essential oil.
In Steps 8 and 9, the safety of the essential oil is evaluated in the context of all congeneric groups and any other related data (e.g., data on the essential oil itself or for an essential oil of similar composition). The procedure organizes the extensive database of information on the essential oil constituents in order to efficiently evaluate the safety of the essential oil under conditions of use. It is important to stress, however, that the guide is not intended to be nor in practice operates as a rigid checklist. Each essential oil that undergoes evaluation is different, and different data will be available for each. The overriding objective of the guide and subsequent evaluation is to ensure that no significant portion of the essential oil should go unevaluated.
220.127.116.11 Prioritization of Essential Oil According to Presence in Food
In Step 1, essential oils are prioritized according to their presence or absence as components of commonly consumed foods. Many essential oils are isolated from plants that are commonly consumed as a food. Little or no safety concerns should exist for the intentional addition of the essential oil to the diet, particularly if intake of the oil from consumption of traditional foods (garlic) substantially exceeds intake as an intentionally added flavoring substance (garlic oil). In many ways, the first step applies the concept of "long history of safe use" to essential oils. That is, if exposure to the essential oil occurs predominantly from consumption of a normal diet a conclusion of safety is straightforward. Step 1 of the guide clearly places essential oils that are consumed as part of a traditional diet on a lower level of concern than those oils derived from plants that are either not part of the traditional diet or whose intake is not predominantly from the diet. The first step also mitigates the need to perform comprehensive chemical analysis for essential oils in those cases where intake is low and occurs predominantly from consumption of food. An estimate of the intake of the essential oil is based on the most recent poundage available from flavor industry surveys and the assumption that the essential oil is consumed by only 10% of the population for an oil having a survey volume <50,000 kg/yr and 100% of the population for an oil having a survey volume >50,000 kg/yr. In addition, the detection limit for constituents is determined based on the daily PCI of the essential oil.
To illustrate the type of data considered in Step 1, consider cornmint oil. Cornmint oil is produced by the steam distillation of the flowering herb of Mentha arvensis. The crude oil contains upwards of 70% (-)-menthol, some of which is isolated by crystallization at low temperature. The resulting dementholized oil is cornmint oil. Although produced mainly in Brazil during the 1970s and 1980s, cornmint oil is now produced predominantly in China and India. Cornmint has a more stringent taste compared to that of peppermint oil, Mentha piperita, but can be efficiently produced and is used as a more cost-effective substitute. Cornmint oil isolated from various crops undergoes subsequent "clean up," further distillation, and blending to produce the finished commercial oil. Although there may be significant variability in the concentrations of individual constituents in different samples of crude essential oil, there is far less variability in the concentration of constituents and congeneric groups in the finished commercial oil. The volume of cornmint oil reported in the most recent U.S. poundage survey is 327,494 kg/yr (Gavin et al., 2008), which is approximately 25% of the potential market of peppermint oil. Because cornmint oil is a high-volume essential oil, it is highly likely that the entire population consumes the annual reported volume, and therefore the daily PCI is calculated based on 100% of the population (280,000,000). This results in a daily PCI of approximately 3.2 mg/person/d (0.0533 mg/kg bw/d) of cornmint oil.
365 days/yr x 280 x 106 persons
Based on the intake of cornmint oil (3204 ^g/d), any constituent present at >0.047% would need to be chemically characterized and quantified:
18.104.22.168 Organization of Chemical Data: Congeneric Groups and Classes of Toxicity
In Step 2, constituents are assigned to one of three structural classes (I, II, or III) based on toxic potential (Cramer et al., 1978). Class I substances contain structural features that suggest a low order of oral toxicity. Class II substances are clearly less innocuous than Class I substances, but do not contain structural features that provide a positive indication of toxicity. Class III substances contain structural features (e.g., an epoxide functional group, unsubstituted heteroaromatic derivatives) that permit no strong presumption of safety, and in some cases may even suggest significant toxicity. For instance, the simple aliphatic hydrocarbon, limonene, is assigned to Structural Class I while elemi-cin, which is an allyl-substituted benzene derivative with a reactive benzylic/allylic position, is assigned to Class III. Likewise, chemically unidentified constituents of the essential oil are automatically placed in Structural Class III, since no presumption of safety can be made.
The toxic potential of each of the three structural classes has been quantified (Munro et al., 1996). An extensive toxicity database has been compiled for substances in each structural class. The database covers a wide range of chemical structures, including food additives, naturally occurring substances, pesticides, drugs, antioxidants, industrial chemicals, flavors, and fragrances. Conservative no-observable-effect-levels (fifth percentile NOELs) have been determined for each class. These fifth per-centile NOELs for each structural class are converted to human exposure thresholds levels by applying a 100-fold safety factor and correcting for mean bodyweight (60/100). The human exposure threshold levels are referred to as thresholds of toxicological concern (TTC). With regard to flavoring substances, the TTC are even more conservative, given that the vast majority of NOELs for flavoring substances are above the 90th percentile. These conservative TTC have since been adopted by the WHO and Commission of the European Communities for use in the evaluation of chemically identified flavoring agents by Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the European Food Safety Authority (EFSA) (JECFA, 1997; EC, 1999).
Step 3 is a key step in the guide. It organizes the chemical constituents into congeneric groups that exhibit common chemical and biological properties. Based on the well-recognized biochemical pathways operating in plants, essentially all of the volatile constituents found in essential oils, extracts, and oleoresins belong to well-recognized congeneric groups. Recent reports (Maarse et al., 1992, 1994, 2000; Nijssen et al., 2003) of the identification of new naturally occurring constituents indicate that newly identified substances fall into existing congeneric groups. The Expert Panel, JECFA, and the European Communities (EC) have acknowledged that individual chemical substances can be evaluated in the context of their respective congeneric group (Smith et al., 2005; JECFA, 1997; EC, 1999). The congeneric group approach provides the basis for understanding the relationship between the biochemical fate of members of a chemical group and their toxicologic potential. Within this framework, the objective is to continuously build a more complete understanding of the absorption, distribution, metabolism, and excretion of members of the congeneric group and their potential to cause systemic toxicity. Within the guidelines, the structural class of each congeneric group is assigned based on the highest structural class of any member of the group. Therefore, if an essential oil contained a group of furanone derivatives that were variously assigned to structural classes II and III, then in the evaluation of the oil the congeneric group would, in a conservative manner, be assigned to Class III.
The types and numbers of congeneric groups in a safety evaluation program are, by no means, static. As new scientific data and information become available, some congeneric groups are combined while others are subdivided. This has been the case for the group of alicyclic secondary alcohols and ketones that were the subject of a comprehensive scientific literature review (SLR) in 1975 (FEMA, 1975). Over the last two decades, experimental data have become available indicating that a few members of this group exhibit biochemical fate and toxicologic potential inconsistent with that for other members of the same group. These inconsistencies, almost without exception, arise at high-dose levels that are irrelevant to the safety evaluation of low levels of exposure to flavor use of the substance. However, given the importance of the congeneric group approach in the safety assessment program, it is critical to resolve these inconsistencies. Additional metabolic and toxico-logic studies may be required to distinguish the factors that determine these differences. Often the effect of dose and a unique structural feature results in utilization of a metabolic activation pathway not utilized by other members of a congeneric group. Currently, evaluating bodies including JECFA, EFSA, and the FEMA Expert Panel have classified flavoring substances into the same congeneric groups for the purpose of safety evaluation.
Step 4 incorporates the available analytical data for constituents in the essential oil into the congeneric group approach. First, the percentages of the individual constituents that comprise each congeneric group are summed. The highest determined percentages for each constituent are used to calculate a total amount for each congeneric group, since this provides the highest possible amount of each congeneric group within the oil. Based on that high percentage and the estimated daily PCI of the essential oil, the daily PCI of the congeneric group from the essential oil is estimated.
In Steps 5, 6, and 7, each congeneric group in the essential oil is evaluated for safety in use. In Step 5, an evaluation of the metabolism and disposition is performed to determine, under current conditions of intake, whether the group of congeneric constituents is metabolized by well-established detoxication pathways to yield innocuous products. That is, such pathways exist for the congeneric group of constituents in an essential oil and safety concerns will arise only if intake of the congeneric group is sufficient to saturate these pathways potentially leading to toxicity. If a significant intoxication pathway exists (e.g., pulegone), this should be reflected in a higher decision-tree class and lower TTC threshold. At Step 6 of the procedure, the intake of the congeneric group relative to the respective TTC for one of the three structural classes (1800 mg/d for Class I; 540 mg/d for Class II; 90 mg/d for Class III; see Table 7.1) is evaluated. If the intake of the congeneric group is less than the threshold for the respective structural class, the intake of the congeneric group presents no significant safety concerns. The group passes the first phase of the evaluation and is then referred to Step 8, the step in which the safety of the congeneric group is evaluated in the context of all congeneric groups in the essential oil.
If, at Step 5, no sufficient metabolic data exist to establish safe excretion of the product, or if activation pathways have been identified for a particular congeneric group, then the group moves to Step 7 and toxicity data are required to establish safe use under current conditions of intake. There are examples where low levels of xenobiotic substances can be metabolized to reactive substances. In the event that reactive metabolites are formed at low levels of intake of naturally occurring substances, a detailed analysis of dose-dependent toxicity data must be performed. Also, if the intake of the congeneric group is greater than the human exposure threshold (suggesting metabolic saturation may occur), then toxicity data are also required. If, at Step 7, a database of relevant toxicological data for a representative member or members of the congeneric group indicates that a sufficient margin of safety exists for the intake of the congeneric group, the members of that congeneric group are concluded to be safe under conditions of use of the essential oil. The congeneric group then moves to Step 8.
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