CB3715673

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ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures Use personal protective equipment. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Remove all sources of ignition. Evacuate personnel to safe areas. Beware of vapors accumulating to form explosive concentrations. Vapors can accumulate in low areas. For personal protection see section Environmental precautions Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided. Methods and materials for containment and cleaning up. Contain spillage, and then collect with an electrically protected vacuum cleaner or by wet-brushing and place in container for disposal according to local regulations. Keep in suitable, closed containers for disposal.

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Citronellal is a monoterpene present in the oil of many species, including Cymbopogon winterianus Jowitt (Poaceae). The present study investigated the effect of citronellal on inflammatory nociception induced by different stimuli and examined the involvement of the NO-cGMP-ATP-sensitive K+ channel pathway. This study used male Swiss mice (n=6 per group) that were treated intraperitoneally with citronellal(25, 50 or 100 mg/kg) 0.5 hr after the subplantar injection of 20 uL of carrageenan (CG; 30 ug/paw), tumor necrosis factor-alpha (TNF-a; 100 pg/paw), prostaglandin E2 (PGE2; 100 ng/paw) or dopamine (DA; 30 ug/paw). The mechanical nociception was evaluated at 0.5, 1, 2 and 3 hr after the injection of the agents, using a digital analgesimeter (von Frey). The effects of citronellal were also evaluated in the presence of L-NAME (30 mg/kg) or glibenclamide (5 mg/kg). At all times, citronellal in all doses inhibited the development of mechanical nociception induced by CG (p<0.001 and p<0.01) and TNF-a (p<0.001, p<0.01, and p<0.05). The citronellal was able to increase the pain threshold in the DA test (p<0.001, p<0.01, and p<0.05) and in the PGE2 test at all times (p<0.001 and p<0.05). L-NAME and glibenclamide reversed the antinociceptive effects of the citronellal at higher doses in the PGE2 test. These data suggest that citronellal attenuated mechanical nociception, mediated in part by the NO-cGMP-ATP-sensitive K+ channel pathway.

Complementary and alternative medicines can be applied concomitantly with conventional medicines; however, little drug information is available on these interactions. Previously, we reported on the inhibitory effects of an extract and monoterpenoids (e.g., (R)-(+)-citronellal) contained in citrus herbs on P-glycoprotein (P-gp) using P-gp-overexpressed LLC-PK1 cells. The objective of the present study was to investigate the effects of (R)-(+)-citronellal on P-gp-mediated transport in the intestinal absorption process in vitro and in vivo. Transcellular transport of [(3)H]digoxin across Caco-2 cell monolayers was measured in the presence or absence of (R)-(+)-citronellal. (R)-(+)-citronellal reduced the basolateral-to-apical transport and efflux ratio for [(3)H]digoxin significantly. Serum concentration-time profiles and pharmacokinetic parameters of digoxin after intravenous and oral administration were analyzed in rats pretreated with oral (R)-(+)-citronellal. The bioavailability of digoxin after oral administration decreased significantly to 75.8% of that after intravenous administration at the same dose. (R)-(+)-citronellal increased the bioavailability of oral digoxin to 99.9% but had no effects on total body clearance, volume of distribution, or elimination rate. These findings suggest that (R)-(+)-citronellal can increase the bioavailability of oral digoxin based on the blockade of P-gp-mediated efflux of digoxin from intestinal epithelia to the lumen in the absorption process.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 650(SRC), determined from a log Kow of 3.83(2) and a regression-derived equation(3), indicates that citronellal is expected to have low mobility in soil(SRC). Volatilization of citronellal from moist soil surfaces may be an important fate process(SRC) given an estimated Henry's Law constant of 2.62X10-4 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Even though the vapor pressure is low environmentally at standard temperature and pressure, estimated as 0.25 mm Hg at 25 °C(SRC), determined from a fragment constant method(3), there is a detectable odor; therefore, citronellal may volatilize from dry soil. Utilizing a Modified Sturm test, 83% biodegradation occurred in 4 weeks(5) suggesting that biodegradation is an important environmental fate process in soil(SRC).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 650(SRC), determined from a log Kow of 3.83(2) and a regression-derived equation(3), indicates that citronellal may adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(4) based upon an estimated Henry's Law constant of 2.62X10-4 atm-cu m/mole(SRC), developed using a fragment constant estimation method(5). Using this Henry's Law constant and an estimation method(4), volatilization half-lives for a model river and model lake are 8 hours and 6 days, respectively(SRC). According to a classification scheme(6), an estimated BCF of 160(SRC), from its log Kow(2) and a regression-derived equation(3), suggests the potential for bioconcentration in aquatic organisms is high(SRC). Utilizing a Modified Sturm test, 83% biodegradation occurred in 4 weeks(7) suggesting that biodegradation is an important environmental fate process in water(SRC).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), citronellal, which has an estimated vapor pressure of 0.25 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 citronellal 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 3 hours(SRC), calculated from its rate constant of 1.2X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). The rate constant for the vapor-phase reaction of citronellal with ozone has been estimated as 4.3X10-16 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). This corresponds to an atmospheric half-life of about 40 minutes at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(4). Citronellal contains chromophores that absorb at wavelengths >290 nm(5) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Citronellal has been found in two commercial samples of cold-pressed oils from the following Florida citrus fruits (in wt %): Valencia orange 0.09 and 0.094; midseason orange (mixture of pineapple and other citrus cultivars) 0.06 and 0.055; tangerine 0.1 and 0.08; and grapefruit 0.091 and 0.077. Two commercial samples of cold-pressed oils from California navel oranges contained citronellal at 0.081 and 0.064%(1).

IDENTIFICATION AND USE: Citronellal is a colorless to slightly yellow liquid with an intense lemon odor. It is used as a flavoring agent and insect repellant. It has been tested as a medication. HUMAN EXPOSURE AND TOXICITY: A maximization test was carried out on 25 volunteers. The material was tested at a concentration of 4% in petrolatum and produced no sensitization reactions. Three cases of eczematous contact-type hypersensitivity to oils of citronella have been recorded. In two instances detailed patch-test studies were made with the ingredients of oil of citronella and some related substances. The essential allergen in oil of citronella was reported to be citronellal. ANIMAL STUDIES: Citronellal applied full strength to intact or abraded rabbit skin for 24 hr under occlusion was moderately irritating. Citronellal injected into white leghorn embryos caused dose-dependent teratogenesis. Morphological malformation occurred mainly in the craniofacial area. Citronellal produced antinociceptive effects in mice and was a strong skin sensitizer in guinea pigs. Mutagenicity was evaluated by the Salmonella/microsome assay (TA97a, TA98, TA100 and TA102 tester strains), without and with metabolic activation. Citronellal was not mutagenic in this test. ECOTOXICITY STUDIES: Citronellal inhibited embryonic development of yellow fever mosquito A aegypti eggs deposited on water. Citronellal causes a severe phytotoxicity on weeds.

/OTHER TERRESTRIAL SPECIES/ Plants produce insect repellents, such as citronellal, which is the main component of citronellal oil. However, the molecular pathways through which insects sense botanical repellents are unknown. Here, we show that Drosophila use two pathways for direct avoidance of citronellal. The olfactory coreceptor OR83b contributes to citronellal repulsion and is essential for citronellal-evoked action potentials. Mutations affecting the Ca(2+)-permeable cation channel TRPA1 result in a comparable defect in avoiding citronellal vapor. The TRPA1-dependent aversion to citronellal relies on a G protein (Gq)/phospholipase C (PLC) signaling cascade rather than direct detection of citronellal by TRPA1. Loss of TRPA1, Gq, or PLC causes an increase in the frequency of citronellal-evoked action potentials in olfactory receptor neurons. Absence of the Ca(2+)-activated K(+) channel (BK channel) Slowpoke results in a similar impairment in citronellal avoidance and an increase in the frequency of action potentials.

/OTHER TERRESTRIAL SPECIES/ Citronellal inhibited embryonic development of yellow fever mosquito A aegypti eggs deposited on water.

/OTHER TERRESTRIAL SPECIES/ We evaluated the acute toxicities and the physiological effects of plant monoterpenoids (eugenol, pulegone, citronellal and alpha-terpineol) and neuroactive insecticides (malathion, dieldrin and RH3421) on flight muscle impulses (FMI) and wing beat signals (WBS) of the blow fly (Phaenicia sericata). Topically-applied eugenol, pulegone, citronellal, and alpha-terpineol produced neurotoxic symptoms, but were less toxic than malathion, dieldrin, or RH3421. Topical application of eugenol, pulegone, andcitronellal reduced spike amplitude in one of the two banks of blow fly dorsolongitudinal flight muscles within 6-8 min, but with citronellal, the amplitude of FMIs reverted to a normal pattern within 1 hr. In contrast to pulegone and citronellal, where impulse frequency remained relatively constant, eugenol caused a gradual increase, then a decline in the frequency of spikes in each muscle bank. Wing beating was blocked permanently within 6-7 min of administering pulegone or citronellal and within 16 mins with eugenol. alpha-Terpineol-treated blow flies could not beat their wings despite normal FMI patterns. The actions of these monoterpenoids on blow fly flight motor patterns are discussed and compared with those of dieldrin, malathion, RH3421, and a variety of other neuroactive substances we have previously investigated in this system. Eugenol, pulegone and citronellal readily penetrate blow fly cuticle and interfere with flight muscle and/or central nervous function. Although there were differences in the effects of these compounds, they mainly depressed flight-associated responses, and acted similarly to compounds that block sodium channels and facilitate GABA action.

/OTHER TERRESTRIAL SPECIES/ The changes of the host-seeking and blood-feeding behavior of Aedes albopictus (Skuse) (Diptera: Culicidae) surviving in a space containing vapors of the spatial repellents geraniol, eugenol, citral, anisaldehyde, or citronellal were evaluated using an arm-in-cage test and a bioassay of bloodmeals on a shaved mouse. The mosquitoes surviving concentrations of geraniol, citral, eugenol, or anisaldehyde at 0.013, 0.025, 0.050, 0.100, and 0.250 ug/cu cm for 24 and 48 hr all showed different degrees of reduction in host-seeking ability. After 48 hr of exposure to 0.250 ug/cu cm geraniol, almost 100% of the mosquitoes lost their host-seeking ability. The next most potent spatial repellent, anisaldehyde, stopped host seeking by > 85.5%. Citronellal did not result in a significant reduction in the host-seeking ability at any concentration level after either 24 or 48 hr of treatment. We also found that reduction of host-seeking ability recovered after various times. The longest recovery time (144 hr) was observed for geraniol after 24 hr at 0.250 ug/cu cm. In the study, geraniol, eugenol, and citral all significantly affected the activation and orientation stages of the blood-feeding behavior. However, only anisaldehyde significantly interrupted the normal blood-feeding of mosquitoes in all stages of behavior. These initial laboratory results clearly showed that anisaldehyde and geraniol could be promising spatial repellents against A. albopictus that they could play a major role in new repellent technology.

EPA has released the first beta version (version 0.5) of the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The beta version of the iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays; Click on the "Chemical Explorer" button on the tool bar to see the data./[USEPA; ICSS Dashboard Application; Available from, as of April 22, 2015: http://actor.epa.gov/dashboard/]

The Koc of citronellal is estimated as 650(SRC), using a log Kow of 3.83(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that citronellal is expected to have low mobility in soil(SRC).

Citronellal has been found in cold-pressed oils from Valencia orange, midseason orange (mixture of pineapple and other citrus cultivars), Calfornia navel orange, tangerine, and grapefruit(1). Citronellal has been reported as a chief constituent in citronella oil(2). It is also found in many other volatile oils, such as lemon, lemon grass, and melissa(2). Citronellal has been found in various tissues and essential oils of numerous plant species including Juniper, Bee balm, Lemon balm, Ginger, Lime, and Lavener(3).

Citronellal occurs in a number of essential oils. The richest sources are Eucalyptus citriodora (up to 85% citronellal content), some chemotypes of Litsea cubeba and citronella (Cymbopogon nardus) [typically 30-40% of the (+)-enantiomer]. Swangi Leaf Oil (Citrus hystrix) is rich in (-)-citronellal, as it accounts for 60-80% of the oil obtained from the leaves. Backhousia citriodora contains up to 80% of the (-)-enantiomer. Natural grades of citronellal are commercially available from Eucalyptus citriodora and E. citronella(1).

/HUMAN EXPOSURE STUDIES/ A maximization test was carried out on 25 volunteers. The material was tested at a concentration of 4% in petrolatum and produced no sensitization reactions.

/CASE REPORTS/ Three cases of eczematous contact-type hypersensitivity to oils of citronella are recorded. In two instances detailed patch-test studies were made with the ingredients of oil of citronella and some related substances. The essential allergen in oil of citronella was reported to be citronellal.

/ALTERNATIVE and IN VITRO TESTS/ Citrus (rutaceous) herbs are often used in traditional medicine and Japanese cuisine and can be taken concomitantly with conventional medicine. In this study, the effect of various citrus-herb extracts on P-glycoprotein (P-gp)-mediated transport was examined in vitro to investigate a possible interaction with P-gp substrates. Component monoterpenoids of the essential oil in Zanthoxyli fructus was screened to find novel P-gp inhibitors. LLC-GA5-COL150 cells transfected with human MDR1 cDNA encoding P-gp were used. Cellular accumulation of [(3)H]digoxin was measured in the presence or absence of P-gp inhibitors or test samples. Aurantii fructus, Evodiae fructus, Aurantii fructus immaturus, Aurantii nobilis pericarpium, Phellodendri cortex, and Zanthoxyli fructus were extracted with hot water (decocted) and then fractionated with ethyl acetate. The cell to medium ratio of [3H]digoxin accumulation increased significantly in the presence of the decoction of Evodiae fructus, Aurantii nobilis pericarpium, and Zanthoxyli fructus, and the ethyl acetate fraction of all citrus herbs used. The ethyl acetate fraction of Zanthoxyli fructus exhibited the strongest inhibition of P-gp among tested samples with an IC50 value of 166 ug/mL. Then its component monoterpenoids, geraniol, geranyl acetate, (R)-(+)-limonene, (R)-(+)-linalool, citronellal, (R)-(+)-citronellal, DL-citronellol, (S)-(-)-beta-citronellol, and cineole, were screened. (R)-(+)-citronellal and (S)-(-)-beta-citronellol inhibited P-gp with IC50 values of 167 uM and 504 uM, respectively. These findings suggest that Zanthoxyli fructus may interact with P-gp substrates and that some monoterpenoids with the relatively lower molecular weight of about 150 such as (R)-(+)-citronellal can be potent inhibitors of P-gp.

/IMMUNOTOXICITY/ Contact hypersensitivity is a major public health concern in most industrial countries, which is why predictive tests which could identify potential allergens are needed. We have established an in vitro approach for the detection of primary immune response. This model uses Langerhans-like dendritic cells (LLDC) derived from cord blood progenitors and autologous T lymphocytes, isolated from the same blood sample. Treatment of day 12-14 LLDC, with strong haptens trinitrobenzene sulfonic acid (TNP), fluorescein isothiocyanate (FITC) or Bandrowski's base (BB), results in the proliferation of T lymphocytes, whereas weak allergens and irritants, such as sodium dodecyl sulfate (SDS) are ineffective. The use of immature (day 8) LLDC and the addition of a 48 hr stage of incubation after hapten contact, result in phenotypic maturation of LLDC in addition to lymphocyte activation in all the cultures with strong haptens. The 48 hr stage of incubation, results in sensitization and in some cases the induction of T cell proliferation to citronellal (1/8), coumarine (1/8) and to a prohapten p-phenylenediamine (pPDA; 2/8). The phenotype of DC after 48 hr of contact with a strong hapten, becomes that of mature DC (CD83(+), CD86(+) and HLA-DR(++)). With fragrance molecules, weak haptens and prohaptens, a comparable phenotype is observed only when T lymphocytes are activated. These data suggest that the unresponsiveness observed with weak haptens, may be the consequence on an incomplete maturation of LLDC.

Citronellal's production and use as a food flavoring ingredient(1) may result in its release to the environment through various waste streams(SRC). It's use as a soap perfume and insect repellent(2) will result in its direct release to the environment(SRC).

Citronellal 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: 1) the quantity added to food does not exceed the amount reasonably required to accomplish its intended physical, nutritive, or other technical effect in food, and 2) when intended for use in or on food it is of appropriate food grade and is prepared and handled as a food ingredient.

Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, exposure, and use to EPA as cited in the preamble in 51 FR 41329. Effective date: 9/30/91; Reporting date: 11/27/91.

Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 6-Octenal, 3,7-dimethyl- is included on this list. Effective date: 9/30/91; Sunset date: 6/30/98.