Absorption, Distribution and Excretion
Male Fischer F344 rats were administered citral (labeled with [14C] at C1 and C2 sites) orally or intravenously at a dose of 5, 50, or 500 mg/kg body weight. Animals were sacrificed 72 hours later, and the radioactivity of tissues and excrement was analyzed. Regardless of dose or route of administration, most of the radiolabeled citral was excreted in urine, feces, and exhaled gases within 24 hours as [14CO2] or [14C] citral. At the lowest oral dose, 83% of the radiolabeled material was recovered within 72 hours (51% in urine, 12% in feces, 17% expelled as sup>14CO₂ in exhaled breath, <1% as sup>14C citral in exhaled breath, and 3% in total tissues). 12 hours post-treatment, sup>14CO₂ production essentially ceased, and sup>14C levels detected in any tissue were very low (<2%). Although the amount oxidized to CO₂ was slightly higher at the lowest dose, this excretion pattern did not change significantly with increasing oral dose. In rats and mice, oral citral was rapidly absorbed from the gastrointestinal tract and resulted in uniform distribution of the label within 12 hours. The radioactive material was rapidly excreted, primarily via the urinary system. There is no evidence of long-term storage in the body. In male Fischer rats, the distribution of citral following intravenous, oral, and transdermal administration was investigated. The distribution and elimination patterns were similar after intravenous or oral administration. Urine was the primary route of excretion of the citral-derived radioactive substance, followed by feces, CO2, and exhalation. However, after transdermal contact, relatively less citral was excreted in urine, while more was excreted in feces, suggesting that citral may undergo first-pass metabolism via the skin. Citral is almost completely absorbed orally; due to its high volatility, most of the dose absorbed through the skin is lost. Citral remaining on the skin is well absorbed. Oral doses (5 to 500 mg/kg) had no effect on drug distribution. Although fecal excretion was less common, approximately 25% of the administered dose was excreted via bile within 4 hours after intravenous administration. Citral metabolism is rapid and extensive. No unmetabolized citral was detected in the blood within 5 minutes after intravenous administration. Repeated exposure to citral resulted in increased bile excretion, but no significant changes were observed in urinary, fecal, or exhaled excretion patterns. This suggests that citral may induce at least one metabolic pathway of its own. The rapid metabolism and excretion of this compound indicate that citral does not undergo significant bioaccumulation.

---

Metabolism/Metabolites
Citral…in experimental animals…is partially converted to so-called Hildebrand acid, in which double ω-oxidation occurs.
Citral is a naturally occurring terpene fatty aldehyde, a mixture of isomers of geranialdehyde and neraldehyde. This study characterized the metabolites of citral in the urine of male F344 rats. Stereoselective oxidation of citral at the C-8 methyl group and the hydrolytic sensitivity of bile and urinary metabolites were investigated. To identify the metabolites, urine was collected on dry ice for 24 hours following a single oral dose of 500 mg/kg of (14)C citral. The drug was rapidly excreted in the urine, with approximately 50% of the dose excreted within 24 hours. Citral is rapidly metabolized and excreted as metabolites, including several acids and a bile glucuronide. Seven urinary metabolites were isolated and identified: 3-hydroxy-3,7-dimethyl-6-octenediaic acid; 3,8-dihydroxy-3,7-dimethyl-6-octenolic acid; 3,9-dihydroxy-3,7-dimethyl-6-octenolic acid; E- and Z-3,7-dimethyl-2,6-octadienoic acid; 3,7-dimethyl-6-octenediaic acid; and E-3,7-dimethyl-2,6-octadienoic acid. Although citral is an α,β-unsaturated aldehyde with potential reactivity, its urinary metabolites do not appear to originate from a double-bond nucleophilic addition reaction, but rather from other metabolic pathways. Reports of in vivo citral metabolism suggest that its primary metabolic pathway is likely the conversion to the corresponding acid, a process possibly catalyzed by aldehyde dehydrogenases. This study prepared mitochondrial and cytoplasmic liver fractions from male Sprague-Dawley rats to assess the in vitro metabolism of citral. No aldehyde dehydrogenase-mediated citral oxidation was observed in either subcellular fraction. Instead, citral was found to be a potent inhibitor of acetaldehyde oxidation catalyzed by low-KM mitochondrial aldehyde dehydrogenases. The in vitro acetaldehyde oxidation rate of this isoenzyme was determined in the presence of citral, yielding a Ki value of 360 nM. Alcohol dehydrogenases in the cytoplasmic fraction were observed to rapidly reduce citral to the corresponding alcohols. In the presence of NADH, the reduction of citral proceeded at two different rates. The difference in the rate of citral reduction by alcohol dehydrogenases may be due to the different affinities of the two citral isomers—geranialdehyde (trans) and neraldehyde (cis)—to this enzyme.

Toxicity Summary
Citral is rapidly absorbed from the gastrointestinal tract. Due to its high volatility, most doses administered via the skin are lost, but residual citral on the skin is still well absorbed. Citral is rapidly metabolized and excreted as metabolites. Urine is the primary route of excretion. This chemical has low acute toxicity in rodents, as its oral or dermal LD50 values exceed 1000 mg/kg. This chemical is irritating to the skin of rabbits but not to the eyes. There is evidence that this chemical is sensitizing to human skin. Multiple repeated oral administration studies have shown that citral did not cause adverse reactions at daily exposures below 1000 mg/kg; however, at daily exposures exceeding 1000 mg/kg, some histological changes occurred in the nasal cavity or forestomach (the site of initial exposure), possibly due to irritation. Male and female F344/N rats were fed diets containing microencapsulated citral at concentrations of 0, 0.63%, 1.25%, 2.5%, 5%, and 10% (corresponding doses: 0, 142, 285, 570, 1140, and 2280 mg/kg/day), respectively, for 14 days. In the 1140 and 2280 mg/kg/day dose groups, mild respiratory epithelial hyperplasia and/or squamous metaplasia were observed in the nasal cavities of both male and female rats, but no inflammatory response was observed. The no-adverse-effect level (NOAEL) was determined to be 570 mg/kg/day. In a preliminary reproductive toxicity screening study [TG 421] conducted by the OECD, Crj:CD (SD) rats were administered the drug via gavage at doses of 0, 40, 200, and 1000 mg/kg/day for 46 days in male rats and at doses of 39–50 days in female rats, including pre-mating, mating, gestation, and day 3 of lactation. In the 1000 mg/kg/day dose group, squamous epithelial hyperplasia, ulceration, and granulation tissue formation were observed in the lamina propria of the forestomach in both male and female rats. Therefore, the no-observed-adverse-effects-level (NOAEL) for repeated-dose toxicity was 200 mg/kg/day. In the aforementioned preliminary reproductive toxicity study, no effects were found on the reproductive capacity, organ weight, reproductive organ histopathology, parturition, or maternal behavior of male and female rats. However, both male and female pups in the 1000 mg/kg group showed decreased body weight. Therefore, the no-observed-adverse-effects-level (NOAEL) for developmental toxicity was 200 mg/kg/day. In a teratogenicity study, pregnant SD rats were exposed to citral for 6 hours daily from days 6 to 15 of gestation at average concentrations of 0, 10, or 34 ppm (vapor) or 68 ppm (aerosol/vapor mixture). Even with maternal effects, no significant teratogenicity was observed at 68 ppm. Therefore, the NOAEL for inhalation teratogenicity at 68 ppm (423 mg/m³) was determined to be 1000 mg/kg. Seven bacterial reversion mutation studies were negative regardless of metabolic activation. Regarding non-bacterial in vitro studies, two Chinese hamster cell chromosomal aberration results were negative, but one sister chromatid exchange result was positive. Furthermore, two rodent in vivo micronucleus assays were negative. Based on this information, the genotoxicity of citral can be considered negative. A study by the National Toxicology Program (NTP) in the United States showed that citral had no carcinogenic activity in male/female rats and male mice, but induced malignant lymphoma in female mice (up to 4000 ppm in rat diet and up to 2000 ppm in mouse diet). Transdermal administration of citral induced only mild prostatic hyperplasia in certain rat strains. However, oral carcinogenicity studies in rats and mice conducted by the NTP did not reveal any lesions (neither neoplastic nor non-neoplastic) in any male reproductive organs (including the prostate). Due to significant differences between different rat strains and the fact that this study was conducted primarily in a single laboratory, the health significance of the effects observed in rat skin studies is unclear.

---

Interactions
…This study aimed to analyze the effects of the immunomodulatory compounds Freund's complete adjuvant (CFA) and cyclosporine A (CsA), alone or in combination with citral, on the induction and extent of prostatic hyperplasia in rats.
Forty-two-day-old adolescent Wistar rats were treated with citral alone or in combination with CFA or CsA for one month. The degree of proliferative lesions was semi-quantitatively analyzed using a tissue scoring method. CsA neither induced proliferative changes nor eliminated the ability of citral to promote proliferative changes, nor affected the degree of lymphocytic exudate in the interstitium. However, CFA itself had a proliferative effect on prostatic epithelium, enhancing citral-induced proliferative changes and even inducing atypical transformation of acinar epithelium. In a two-stage skin carcinogenesis study in hairless mice, we tested the ability of citral to regulate tumorigenesis. First, 0.1 μmol of dimethylbenzanthracene was injected into the dorsal skin of female skh/hr1 mice, followed by application of 10 nmol tetradecanoylphorbol-13-acetate (TPA) twice weekly for 20 weeks to promote tumorigenesis. Before each TPA application, 0, 1, or 10 μmol of citral, respectively, was administered. The results showed that citral had a dose-dependent inhibitory effect on tumorigenesis in the TPA-promoted tumorigenesis group. Citral inhibited the conversion of retinol to retinoic acid in the mouse epidermis. Since skin cancer development is sensitive to retinoid status, and retinoic acid may be the active form of vitamin A in the epidermis, this study conducted a two-stage skin cancer development model in hairless mice to test the ability of citral to regulate tumorigenesis. First, 0.1 μmol of dimethylbenzanthracene was injected into the dorsal skin of female SKH/HRL mice, followed by application of 10 nmol tetradecanoylphorbol-13-acetate (TPA) twice weekly for 20 weeks to promote tumorigenesis. Before each TPA application, mice in each group were given 0, 1, or 10 μmol of citral, respectively. The results showed that citral had a dose-dependent inhibitory effect on TPA-promoted tumorigenesis. After 10 weeks of induction, the tumor incidence rates in mice treated with 0, 1, and 10 μmol citral were 88%, 72%, and 60%, respectively, with the number of tumors per affected mouse (mean ± standard deviation) being 7.3 ± 6.6, 3.9 ± 4.2, and 3.7 ± 3.5, respectively. After 15 weeks of induction, the tumor incidence rates in each group were 96%, 96%, and 84%, respectively, with the number of tumors per affected mouse being 9.5 ± 6.8, 7.2 ± 4.6, and 4.5 ± 3.3, respectively. The high-dose citral group showed a significant reduction in tumor number. The study was terminated after 20 weeks of intensive treatment, with all mice exhibiting at least one tumor, but fewer tumors per affected mouse in the citral-treated group.

---

Non-human toxicity values
Oral LD50 in mice: 1440 mg/kg body weight
Oral LD50 in mice: 3297 mg/kg body weight
Oral LD50 in male mice (synthetic citral): 2007 mg/kg body weight
Oral LD50 in rats: 4950 mg/kg body weight
For more non-human toxicity values (complete data) for citral (12 in 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 is a clear, yellow liquid with a lemon-like aroma. It is less dense than water and insoluble in water. Ingestion is toxic. It is used in the manufacture of other chemicals. Geranialdehyde is a monoterpenoid compound with the structure (2E,6E)-octyl-2,6-dienal, substituted with methyl groups at positions 3 and 7. It is a plant metabolite and volatile oil component. It is an enal, monoterpenoid, and polyisopreneal. Citral has been reported in Pectis brevipedunculata, Boesenbergia rotunda, and other organisms with relevant data. Citral is a metabolite found or produced in Saccharomyces cerevisiae.
See also: Neraldehyde (note moved to)...View more...

---

Mechanism of Action
Low concentrations of citral (3,7-dimethyl-2,6-octadienal)...inhibit the E1, E2, and E3 isoenzymes of human aldehyde dehydrogenase (EC 1.2.1.3). This inhibition is reversed upon dilution and prolonged incubation in the presence of NAD+; NADH and geraniol are generated simultaneously. Therefore, citral is both an inhibitor and a substrate. The Km values of citral are: E1 4 μM, E2 1 μM, E3 0.1 μM; the highest Vmax value is for E1 (73 nmol/min/mg), followed by E2 (17 nmol/min/mg), and the lowest is for the E3 isoenzyme (0.07 nmol/min/mg). Citral is a 1:2 mixture of two isomers: the cis isomer neraldehyde and the trans isomer geraniol; the latter is structurally similar to physiologically important retinoids. All three isoenzymes utilize both isomers; however, high-performance liquid chromatography and enzyme kinetics experiments show that the E1 isoenzyme prefers the trans isomer geraniol. For the E1 isoenzyme, both geraniol and neraldehyde follow Michaelis-Menten kinetics; for the E2 isoenzyme, only neraldehyde follows Michaelis-Menten kinetics. Using the E2 isoenzyme and geraniol, an S-shaped saturation curve with an S_0.5 of approximately 50 nM was observed; n values between 2 and 2.5 indicate positive cooperativity. Geraniol is a better substrate and inhibitor than neraldehyde. The lower V_max value of citral is likely due to the slow formation of the thiohemiacetal reaction intermediate or its decomposition via hydride transfer, making citral an excellent inhibitor, with its selectivity enhanced by the lower K_m value. The Vmax of citral with the E1 isoenzyme was higher than that with the E2 and E3 isoenzymes, which explains its rapid recovery after inhibition by citral and suggests that E1 may be an enzyme involved in the metabolism of citral in vivo. We tested the effects of essential oil components on the neurophysiology of the American cockroach (Periplaneta americana) and the discoid cockroach (Blaberus discoidalis)... Geraniol and citral had similar inhibitory effects, but increased spontaneous firing at lower doses (threshold 2.5 x 10⁻⁴ M). Intracellular recordings in isolated terminal ventral ganglia of the American cockroach revealed similar effects in dorsal unpaired midline (DUM) neurons... Citral produced a biphasic effect (excitation at 10⁻⁴ M, inhibition at 2 x 10⁻³ M). All essential oils reduced the excitability of resting DUM neurons depolarized by electrical current... All essential oils reduced action potential downshoot. Low doses of citral and geraniol (threshold approximately 10⁻⁴ M) reversibly increased the frequency of spontaneous foregut contractions and eliminated them (as well as responses to electrical stimulation) at 2 x 10⁻³ M.

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.

---

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.

---

View More

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.

---

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.

---

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