Absorption, Distribution and Excretion
Male Fischer F344 rats were given citral labelled with 14C at the C1 and C2 positions in a single oral dose of 5, 50, or 500 mg/kg bw or an intravenous dose of 5 mg/kg bw. After 72 h, the animals were sacrificed and tissues and excreta analyzed for radioactivity. Most radiolabel was excreted in the urine, feces, and expired air as 14CO2 or [14C]citral within 24 hr, regardless of the dose or route of administration. At the lowest oral dose, 83% of the radiolabel was recovered within 72 hr (51% in urine, 12% in feces, 17% as expired 14CO2, <1% as expired [14C]citral, and 3% in total tissues). Production of 14CO2 essentially ceased 12 hr after treatment, and the amount of 14C found in any tissue was very small (<2%). This excretion profile did not change much with increasing oral dose, although ... oxidation to CO2 was somewhat greater at the lowest dose.
In rat & mouse orally admin citral was rapidly absorbed from gi tract, resulting in uniform distribution of label throughout body of mouse by 12 hr. Radioactivity was excreted rapidly, major route being urinary tract. No evidence for long-term storage in body.
The disposition of citral was studied in male Fischer rats after iv, po, and dermal treatments. The pattern of distribution and elimination was the same after iv or oral exposure. Urine was the major route of elimination of citral-derived radioactivity, followed by feces, (14)C02, and expired. However, after dermal exposure, relatively less of the material was eliminated in the urine and more in the feces, suggesting a role for first-pass metabolism through the skin. Citral was almost completely absorbed orally; due to its extreme volatility, much of an applied dermal dose was lost. The citral remaining on the skin was fairly well absorbed. No effect of oral dose, from 5 to 500 mg/kg, was detected on disposition. Although the feces was a minor route of excretion, approximately 25% of the administered dose was eliminated via the bile within 4 hr of an iv dose. The metabolism of citral was both rapid and extensive. Within 5 min of an iv dose, no unmetabolized citral could be detected in the blood. Repeated exposure to citral resulted in an increase in biliary elimination, without any significant change in the pattern of urinary, fecal, or exhaled excretion. This suggests that citral may induce at least one pathway of its own metabolism. The rapid metabolism and excretion of this compound suggest that significant bioaccumulation of citral would not occur.

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Metabolism / Metabolites
Citral ... in experimental animals ... is converted in part to the so-called Hildebrandt acid in which a double omega oxidation has taken place.
Citral is a naturally occurring aliphatic aldehyde of the terpene series and is an isomeric mixture of geranial and neral. In this study, urinary metabolites of citral in male F344 rats were characterized. Stereospecific oxidation of citral at the C-8 methyl was investigated, as was the hydrolytic sensitivity of biliary and urinary metabolites. For metabolite identification, urine was collected over dry ice for 24 hr after a single po 500 mg/kg dose of (l4)C citral. Elimination in urine was rapid, with approximately 50% of the dose excreted within 24 hr. Citral was rapidly metabolized and excreted as metabolites, including several acids and a biliary glucuronide. Seven urinary metabolites were isolated and identified: 3-hydroxy-3,7-dimethyl-6-octenedioic acid; 3,8-dihydroxy-3,7-dimethyl-6-octenolc acid; 3,9-dihydroxy-3,7-dimethyl-6-octenolc acid; E- and Z-3,7-dimethyl-2,6-octadienedioic acid; 3,7-dimethyl-6-octenedioic acid; and E-3,7-dimethyl-2,6-octadienoic acid. Although citral is an alpha,beta-unsaturated aldehyde and has the potential of being reactive, the urinary metabolites of citral appear to arise from metabolic pathways other than nucleophilic addition to the double bond.
Reports of the in vivo metabolism of citral suggest that a primary route of metabolism is conversion to the corresponding acid presumably by aldehyde dehydrogenases. In the present study, hepatic mitochondrial and cytosolic fractions were prepared from male Sprague-Dawley rats to assess in vitro metabolism of citral. Evidence of aldehyde dehydrogenases-mediated citral oxidation was not seen in either subcellular fraction. On the contrary, citral was found to be a potent inhibitor of acetaldehyde oxidation by the low-KM mitochondrial form of aldehyde dehydrogenases. Measurement of the in vitro acetaldehyde oxidation rates of this isozyme in the presence of citral lead to the estimation of a Ki of 360 nM. It was observed that citral was readily reduced to the corresponding alcohol by alcohol dehydrogenase in the cytosolic fraction. The reduction of citral in the presence of NADH proceeded at two distinct rates. It is possible that the differential alcohol dehydrogenase-mediated reduction rates of citral are the result of varying affinities for the enzyme of two citral, isomers, geranial (trans) and neral (cis).

Toxicity Summary
Citral was rapidly absorbed from the gastro -intestinal tract. Much of an applied dermal dose was lost due to its extreme volatility, but the citral remaining on the skin was fairly well absorbed. Citral was rapidly metabolized and excreted as metabolites. Urine was the major route of elimination. Acute toxicity of this chemical is low in rodents because the oral or dermal LD50 values were more than 1000 mg/kg. This chemical is irritating to skin and not irritating to eyes in rabbits. There is some evidence that this chemical is a human skin sensitizer. Several repeated dose oral studies show no adverse effect of citral at less than 1,000 mg/kg/day exposure and some histological changes in the nasal cavity or forestomach, the first exposure sites, probably due to irritation, at more than 1,000 mg/kg/day. Male and female F344/N rats received microencapsulated citral in feed at concentrations of 0, 0.63, 1.25, 2.5, 5 and 10% (resultant doses: 0, 142, 285, 570, 1,140 and 2,280 mg/kg/day) for 14 days. Minimal to mild hyperplasia and/or squamous metaplasia of the respiratory epithelium was observed in nasal cavity without inflammatory response at 1,140 and 2,280 mg/kg/day of both sexes. The NOAEL was established at 570 mg/kg/day. In an OECD preliminary reproduction toxicity screening test [TG 421], citral was administered to Crj:CD (SD) rats by gavage at doses of 0, 40, 200 and 1,000 mg/kg/day in males for 46 days and in females for 39- 50 days including before and through mating and gestation periods and until day 3 of lactation. Squamous hyperplasia, ulcer and granulation in lamina propria were observed in the forestomach at 1,000 mg/kg/day of both sexes. Therefore, the NOAEL for repeated dose toxicity was 200 mg/kg/day for both sexes. As for reproductive toxicity in the above preliminary reproductive study, no effects were detected in reproductive ability, organ weights or histopathology of the reproductive organs of both sexes, and delivery or maternal behavior. However, body weights of male and female pups were reduced in the 1000 mg/kg group. Therefore, an oral NOAEL for developmental toxicity was 200 mg/kg/day. In a teratogenicity study, SD pregnant rats were exposed to citral by inhalation for 6 hr/day on gestation days 6-15 at mean concentration of 0, 10 or 34 ppm as vapour, or 68 ppm as an aerosol/vapour mixture. Even in the presence of the maternal effects, no significant teratogenicity was noted at 68 ppm. An inhalation NOAEL of teratogenicity was established at 68 ppm (423 mg/m3). Seven bacterial reverse mutation studies indicate negative results with and without metabolic activation. As for non-bacterial in vitro study, two chromosomal aberration results in Chinese hamster cells are negative however one positive result in sister chromatid exchange is given in the same cells. Add itionally, two in vivo micronucleus tests in rodents indicate negative results. Based on the above information, the genotoxic potential of citral can be considered to be negative. A NTP study shows that there was no evidence of carcinogenic activity in male/female rats and male mice but some evidence of malignant lymphoma in female mice (up to 4,000 ppm in feed in rats and up to 2,000 ppm in feed in mice). Dermal application of citral induces prostate hyperplasia with low severity only in some strains of rats. However, the NTP oral carcinogenicity studies in rats and mice found no evidence of lesions (neoplastic or non-neoplastic) in any male reproductive organ, including the prostate. The health significance of the effects seen in the dermal studies in rats is uncertain due to dramatic strain differences and it is noted that the work has primarily been performed in a single laboratory.

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Interactions
... The aim of the present study was to analyze the effect of the immunomodulator compounds, Complete Freund Adjuvant (CFA) and cyclosporin A (CsA), administered alone or together with citral on the induction and extent of rat prostatic hyperplasia. Adolescent Wistar rats (42 days old) were given citral alone or combined with CFA or CsA for one month. Semiquantitative analysis of the extent of the hyperplastic lesions was made with the histoscore protocol. CsA did not induce hyperplastic changes or abolish the ability of citral to promote hyperplastic changes or to affect the extent of the lymphocytic exudate in the stroma. CFA itself, however, had a proliferative action on the prostatic epithelium, and it augmented the hyperplastic changes induced by citral and even induced atypical transformations of the acinar epithelium.
The ability of citral to modulate tumor promotion was tested in a two-stage skin carcinogenesis study in hairless mice. The dorsal skins of female skh/hr1 mice were initiated with 0.1 umol dimethylbenzanthracene, and tumors were promoted by twice-weekly application of 10 nmol of tetradecanionyl-phorbol-13-acetate (TPA) for 20 weeks. Prior to each TPA application, citral was given with 0, 1 or 10 umol. Citral had a dose-dependent inhibitory effect on tumor production in the TPA promoted groups.
Citral inhibits the formation of retinoic acid from retinol in mouse epidermis. Since skin-carcinogenesis is sensitive to retinoid status, and retinoic acid may be the active form of vitamin A in the epidermis, citral was tested for its ability to modulate tumor promotion in a two-stage skin-carcinogenesis study in hairless mice. The dorsal skins of female SKH/HRL mice were initiated with 0.1 umol dimethylbenzanthracene, and tumors were promoted by twice-weekly application of l0 nmol of tetradecanoylphorbol-13-acetate (TPA) for 20 weeks. Prior to each TPA application groups were dosed with 0, l umol or 10 umol citral. Citral had a dose-dependent inhibitory effect on tumor-production in the TPA promoted groups. At 10 weeks of promotion the percentage of mice with tumors were 88%, 72% and 60%, for the 0, 1 and l0 umol citral treated groups, and the numbers (mean + or- SD) of tumors per affected animal were 7.3 + or - 6.6, 3.9 + or - 4.2, and 3.7 + or - 3.5, respectively. At 15 weeks of promotion the tumor incidence was 96%, 96% and 84%, respectively, and the number of tumors per affected animal were 9.5 + or - 6.8, 7.2 + or - 4.6 and 4.5 + or - 3.3, respectively. The mice in the high dose citral group had significantly fewer tumors. When the study was terminated at 20 weeks of promotion all mice had at least one tumor, but the number of tumors per affected mouse were lower in the citral treated groups.

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Non-Human Toxicity Values
LD50 Mouse oral 1440 mg/kg bw
LD50 Mouse oral 3297 mg/kg bw
LD50 Mouse male oral 2007 mg/kg bw (synthetic citral)
LD50 Rat oral 4950 mg/kg bw
For more Non-Human Toxicity Values (Complete) data for CITRAL (12 total), please visit the HSDB record page.

[1]. Anti-hyperalgesic and anti-inflammatory effects of citral with β-cyclodextrin and hydroxypropyl-β-cyclodextrin inclusion complexes in animal models. Life Sci. 2019 Jul 15;229:139-148.

[2]. Citral inhibits cell proliferation and induces apoptosis and cell cycle arrest in MCF-7 cells. Fundam Clin Pharmacol. 2009 Oct;23(5):549-56.

[3]. Citral presents cytotoxic and genotoxic effects in human cultured cells. Drug Chem Toxicol. 2020 Jul;43(4):435-440.

[4]. Citral protects against LPS-induced endometritis by inhibiting ferroptosis through activating Nrf2 signaling pathway. Inflammopharmacology. 2023 Jun;31(3):1551-1558.

Citral appears as a clear yellow colored liquid with a lemon-like odor. Less dense than water and insoluble in water. Toxic by ingestion. Used to make other chemicals.
Geranial is a monoterpenoid that is (2E,6E)-octa-2,6-dienal substituted by methyl groups at positions 3 and 7. It has a role as a plant metabolite and a volatile oil component. It is an enal, a monoterpenoid and a polyprenal.
Citral has been reported in Pectis brevipedunculata, Boesenbergia rotunda, and other organisms with data available.
Citral is a metabolite found in or produced by Saccharomyces cerevisiae.
See also: Neral (annotation moved to) ... View More ...

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Mechanism of Action
Low concentrations of citral (3,7-dimethyl-2,6-octadienal), ... inhibited E1, E2 and E3 isozymes of human aldehyde dehydrogenase (EC1.2.1.3). The inhibition was reversible on dilution and upon long incubation in the presence of NAD+; it occurred with simultaneous formation of NADH and of geranic acid. Thus, citral is an inhibitor and also a substrate. Km values for citral were 4 microM for E1, 1 microM for E2 and 0.1 microM for E3; Vmax values were highest for E1 (73 nmol/min/mg), intermediate for E2 (17 nmol/min/mg) and lowest (0.07 nmol/min/mg) for the E3 isozyme. Citral is a 1 : 2 mixture of isomers: cis isomer neral and trans isomer, geranial; the latter structurally resembles physiologically important retinoids. Both were utilized by all three isozymes; a preference for the trans isomer, geranial, was observed by HPLC and by enzyme kinetics. With the E1 isozyme, both geranial and neral, and with the E2 isozyme, only neral obeyed Michaelis-Menten kinetics. With the E2 isozyme and geranial sigmoidal saturation curves were observed with S0.5 of approximately 50 nM; the n-values of 2-2.5 indicated positive cooperativity. Geranial was a better substrate and a better inhibitor than neral. The low Vmax, which appeared to be controlled by either the slow formation, or decomposition via the hydride transfer, of the thiohemiacetal reaction intermediate, makes citral an excellent inhibitor whose selectivity is enhanced by low Km values. The Vmax for citral with the E1 isozyme was higher than those of the E2 and E3 isozymes which explains its fast recovery following inhibition by citral and suggests that E1 may be the enzyme involved in vivo citral metabolism.
Essential oil constituents were tested for their neurophysiological effects in Periplaneta americana and Blaberus discoidalis /cockroaches/ ... Geraniol and citral had similar depressive effects but increased spontaneous firing at lower doses (threshold 2.5 x 10-4 M). Similar effects occurred in dorsal unpaired median (DUM) neurons, recorded intracellularly in the isolated terminal abdominal ganglion of P. Americana. ... citral produced biphasic effects (excitation at 10-4 M, depression at 2 x 10-3 M). All oils decreased excitability of silent DUM neurons that were depolarised by applied current... All oils reduced spike undershoot. Low doses of citral and geraniol (threshold ca. 10-4 M) reversibly increased the frequency of spontaneous foregut contractions and abolished them at 2 x 10-3 M (together with response to electrical stimulation).

C10H16O

152.2334

152.12

5392-40-5

638011

Colorless to light yellow liquid

0.9±0.1 g/cm3

229.0±9.0 °C at 760 mmHg

< -10ºC

101.7±0.0 °C

0.1±0.5 mmHg at 25°C

1.457

3.17

0

1

4

11

171

0

O=C([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])/C(/[H])=C(\C([H])([H])[H])/C([H])([H])[H]

WTEVQBCEXWBHNA-JXMROGBWSA-N

InChI=1S/C10H16O/c1-9(2)5-4-6-10(3)7-8-11/h5,7-8H,4,6H2,1-3H3/b10-7+

(2E)-3,7-dimethylocta-2,6-dienal

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~328.45 mM)
H2O : ~1 mg/mL (~6.57 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (16.42 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (16.42 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (16.42 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 50 mg/mL (328.45 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)