(+)-Nootkatone

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 2210(SRC), determined from a structure estimation method(2), indicates that nootkatone is expected to have slight mobility in soil(SRC). Volatilization of nootkatone from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.4X10-4 atm-cu m/mole(SRC), using a fragment constant estimation method(2). Nootkatone is bicyclic terpene and screening test results of other bicyclic terpenes indicate the compounds are generally biodegradable, but not readily biodegradable(3).

FIELD STUDY: Nootkatone is reported to rapidly turn to vapor when applied in the field as an essential oil for bio-based pesticide applications(3). Field applications of nootkatone did not last more than 3 days before pest control broke down. Tests for residual activity showed that 95% of the nootkatone (when applied as an emulsifiable concentrate) had disappeared by 5 days versus only 45% for a lignin-encapsulated nootakatone mixture, indicating it had substantially slowed the oil's volatility(1).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 2210(SRC), determined from a structure estimation method(2), indicates that nootkatone is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon an estimated Henry's Law constant of 1.4X10-4 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 13.5 hours and 8.6 days, respectively(SRC). According to a classification scheme(4), an estimated BCF of 159(SRC), from its log Kow of 3.84(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is high(SRC). Nootkatone is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(3). Nootkatone is an olefin and olefins in surface waters exposed to sunlight react with photo-oxidants (such as hydroxyl radicals, peroxy radicals and singlet oxygen) with a half-life on the order of 25 days(5). Nootkatone is bicyclic terpene and screening test results of other bicyclic terpenes indicate the compounds are generally biodegradable, but not readily biodegradable(6).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), nootkatone, which has an estimated vapor pressure of 0.003 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase nootkatone is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 2.6 hours(SRC), calculated from its rate constant of 1.5X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). Vapor-phase nootkatone is degraded in the atmosphere by reaction with ozone; the half-life for this reaction in air is estimated to be 12 hours(SRC), calculated from its rate constant of 2.3X10-17 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). Vapor-phase nootkatone is also degraded in the atmosphere by reaction with nitrate radicals; the half-life for this reaction in air is estimated to be 0.8 hours(SRC), calculated from a rate constant of 1.0X10-12 cu cm/molecule-sec at 24 °C(SRC) for analogous olefins(3). The nitrate radical (NO3) is the dominant atmospheric oxidant during the night-time in most atmospheric environments(4), therefore, night-time degradation appears to be a major fate process for nootkatone(SRC). Nootkatone contains chromophores that absorb at wavelengths >290 nm(5) and, therefore, may be susceptible to direct photolysis by sunlight.

Nootkatone was detected in Valencia and California navel orange citrus oils at levels of 0.015-0.051 wt%(1). Nootkatone has been identified in grapefruit, oranges and lemons(2); it is an important part of the taste of grapefruit(2). Reported to occur in canned orange juice(3).

IDENTIFICATION AND USE: Nootkatone forms crystals; however, commercial product is a colorless to yellowish liquid. It is used in beverages to impart grapefruit flavor; in fragrance compositions with other citrus oils. Potential bio-based pesticide to kill ants, termites, mosquitoes, cockroaches, and ticks, including Ixodes scapularis (blacklegged tick), whose bite can transmit bacteria that cause Lyme disease in humans and other animals. HUMAN EXPOSURE AND TOXICITY: No human data were found. ANIMAL STUDIES: In a 28-day study, rats (male and female) were given nootkatone at a dose of 10 mg/kg bw per day by oral gavage. No clinically observable signs of toxicity were reported. Histopathological examination revealed accumulation of globular eosinophilic material in the tubular epithelium of male rats treated with nootkatone at a dose of 10 mg/kg bw per day. This finding is consistent with the presence of hyaline droplet nephropathy, which results from the excessive accumulation of alpha-2u-globulin in renal proximal tubular epithelial cells. Accumulation of alpha-2u-globulin in the proximal tubular epithelium is considered to be of no relevance to humans. ECOTOXICITY STUDIES: Encapsulation of nootkatone improved toxicity for tick control, reduced nootkatone volatility, and reduced plant phytotoxicity.

/PLANTS/ Nootkatone is a component of grapefruit oil that is toxic to the disease-vectoring tick, Ixodes scapularis Say, but unfortunately causes phytotoxicity to treated plants and has a short residual activity due to volatility. We prepared a lignin-encapsulated nootkatone formulation to compare with a previously used emulsifiable formulation for volatility, plant phytotoxicity, and toxicity to unfed nymphs of I. scapularis. Volatility of nootkatone was measured directly by trapping nootkatone vapor in a closed system and indirectly by measuring nootkatone residue on treated filter paper after exposure to simulated sunlight (Xenon). After 24 hr in the closed system, traps collected only 15% of the nootkatone applied as the encapsulated formulation compared with 40% applied as the emulsifiable formulation. After a 1-hr light exposure, the encapsulated formulation retained 92% of the nootkatone concentration compared with only 26% retained by the emulsifiable formulation. For plant phytotoxicity, cabbage, Brassica oleracea L., leaves treated with the encapsulated formulation expressed less necrosis, retaining greater leaf weight compared with leaves treated with the emusifiable formulation. The nootkatone in the emulsifiable formulation was absorbed by cabbage and oat, Avena sativa L., plants (41 and 60% recovered 2 hr after application, respectively), as opposed to 100% recovery from the plants treated with encapsulated nootkatone. Using a treated vial technique, encapsulated nootkatone was significantly more toxic to I. scapularis nymphs (LC50 = 20 ng/sq cm) compared with toxicity of the emulsifiable formulation (LC50 = 35 ng/sq cm). Thus, the encapsulation of nootkatone improved toxicity for tick control, reduced nootkatone volatility, and reduced plant phytotoxicity.

White grapefruit oil obtained from the varieties Marsh seedless and Duncan, grown in Florida, contain about 0.5% ketone content that is mainly nootkatone(1). Nootkatene is readily obtainable from the wood of Chamaecyparis nootkatensis(2). Nootkatone has been detected in Alaska yellow cedar trees(3) and vetiver grass(4). Reportedly found in grapefruit oil and juice and in oils of bergamont, lemon, lime, orange and tangerine(5). Nootkatone is reported to be a major component of Alaska cedar (Callitropsis nootkatensis) heartwood essential oil(6). Nootkatone was identified in Cyperus rotundus, a well-known oriental traditional medicine, which is species of sedge plant(7).

Nootkatone detections in plants(1).[Table#8267]

Using a structure estimation method based on molecular connectivity indices(1), the Koc of nootkatone can be estimated to be 2210(SRC). According to a classification scheme(2), this estimated Koc value suggests that nootkatone is expected to have slight mobility in soil.

Nootkatone's production and use as a flavoring ingredient to impart grapefruit flavor in beverages and use in fragrance compositions(1) may result in its release to the environment through various waste streams(SRC). Its potential use as a bio-based pesticide(2) would result in its direct release to the environment(SRC).

An estimated BCF of 159 was calculated in fish for nootkatone(SRC), using a log Kow of 3.84(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is high(SRC), provided the compound is not metabolized by the organism(SRC).

The Henry's Law constant for nootkatone is estimated as 1.4X10-4 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that nootkatone is expected to volatilize from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 13.5 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 8.6 days(SRC). Nootkatone's Henry's Law constant indicates that volatilization from moist soil surfaces may occur(SRC). Nootkatone is reported to rapidly turn to vapor when applied in the field as an essential oil for bio-based pesticide applications(3); encapsulating the nootkatone in lignin slows the environmental loss in field application(3). Volatility measurements in a closed system for 24-hours found 40% of the applied nootkatone volatilized from emulsifiable formulations, but only 15% from encapsulated formulations(4).

Nootkatone is a food additive permitted for direct addition to food for human consumption as a synthetic flavoring substance and adjuvant in accordance with the following conditions: a) they are used in the minimum quantity required to produce their intended effect, and otherwise in accordance with all the principles of good manufacturing practice, and b) they consist of one or more of the following, used alone or in combination with flavoring substances and adjuvants generally recognized as safe in food, prior-sanctioned for such use, or regulated by an appropriate section in this part.