(+)-Pulegone

152.23

152.23

201-943-2

4LF2673R3G

DTXSID2025975

Oil|Oily liquid

2914299000

17.1

2.8

Clear colorless to yellow Liquid

0.93808 g/cm³ @ Temp: 16.9 °C

<25 °C

224 °C

185 °F

1.470

Miscible with alcohol. ether, chloroform

2-8°C

138 mm Hg ( 25 °C)

LD50 orally in Rabbit: 470 mg/kg LD50 dermal Rabbit 3090 mg/kg

D20 +21°; 20546 +28.2°

Pleasant odor, midway between peppermint and camphor

Henry's Law constant = 5.87X10-5 atm-cu m/mol at 25 °C (est)

Liquid. BP: 78-80 °C at 7 mm Hg. Index of refraction: 1.4856 at 16 °C/D. UV max (alcohol): 253.13 nm (log e 3.86) /Pulegone +/- form/|Liquid. BP: 104-108 °C at 20 mm Hg. Specific optical rotation: -22.5 deg at 23 °C/D (neat) /Pulegone (-) form/|Hydroxyl radical reaction rate constant = 1.12X10-10 cu cm/molec-sec at 25 °C (est)

Ⅲ

6.1(b)

2810

3

22

23-24/25

OT0261000

Xn

Stable under recommended storage condition /(R)-(+)-Pulegone/

P273-P301 + P312 + P330

H302-H351-H412

Strong oxidizing agents. /(R)-(+)-Pulegone/|/Conditions to avoid/ Heat, flames and sparks. /(R)-(+)-Pulegone/

Pulegone 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.

Final Report on the Safety Assessment of Mentha Piperita (Peppermint) Oil, Mentha Piperita (Peppermint) Leaf Extract, Mentha Piperita (Peppermint) Leaf, and Mentha Piperita (Peppermint); International Journal of Toxicology 20 (Suppl 3): 61-73 (2001).

|Warning|H302 (96.73%): Harmful if swallowed [Warning Acute toxicity, oral]|P264, P270, P301+P312, P330, and P501|Aggregated GHS information provided by 336 companies from 4 notifications to the ECHA C&L Inventory.|Danger|H301: Toxic if swallowed [Danger Acute toxicity, oral]|P201, P202, P260, P264, P270, P281, P301+P310, P308+P313, P314, P321, P330, P405, and P501

Wear self contained breathing apparatus for fire fighting if necessary. /(R)-(+)-Pulegone/|For small (incipient) fires, use media such as "alcohol" foam, dry chemical, or carbon dioxide. For large fires, apply water from as far as possible. Use very large quantities (flooding) of water applied as a mist or spray; solid streams of water may be ineffective. Cool all affected containers with flooding quantities of water. /(R)-(+)-Pulegone/

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 (see section 13). Keep in suitable, closed containers for disposal. /(R)-(+)-Pulegone/

Use personal protective equipment. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Remove all sources of ignition. Beware of vapors accumulating to form explosive concentrations. Vapors can accumulate in low areas. /(R)-(+)-Pulegene/

Occupational exposure to pulegone may occur through inhalation and dermal contact with this compound at workplaces where pulegone is produced or used. Monitoring data indicate that the general population may be exposed to pulegone via ingestion of plants and consumer products containing pulegone. (SRC)

Intraperitoneal injection of R-(+)-pulegone (pulegone), the main constituent of pennyroyal oil, to ddY mice caused extensive liver injury as characterized by an increase in serum glutamic pyruvic transaminase (GPT) activity and centrilobular necrosis of hepatocytes. Treatments of mice with the cytochrome P-450 enzyme inhibitors, SKF-525A, metyrapone, piperonyl butoxide, and carbon disulfide (CS2), prevented or markedly alleviated the hepatotoxicity of pulegone. These results are compatible with the view that some metabolite of pulegone is responsible for the liver injury in mice.|Pennyroyal oil ingestion has been associated with severe hepatotoxicity and death. The primary constituent, R-(+)-pulegone, is metabolized via hepatic cytochrome P450 to toxic intermediates. The purpose of this study was to assess the ability of the specific cytochrome P450 inhibitors disulfiram and cimetidine to mitigate hepatotoxicity in mice exposed to toxic levels of R-(+)-pulegone. 20-g female BALB/c mice were pretreated with either 150 mg/kg of cimetidine intraperitoneal (IP), 100 mg/kg of disulfiram IP, or both. After one hour, mice were administered 300 mg/kg of pulegone IP and were killed 24 hours later. Data were analyzed using ANOVA. Post-hoc t-tests used Bonferroni correction. There was a tendency for lower serum glutamate pyruvate transaminase in the disulfiram and cimetidine groups compared with the R-(+)-pulegone group. The differences were significant for both the cimetidine and the combined disulfram and cimetidine groups compared with the R-(+)-pulegone group. Pretreatment with the combination of disulfiram and cimetidine most effectively mitigated R-(+)-pulegone-induced hepatotoxicity. Within the limitations of a pretreatment animal model, the combination of cimetidine and disulfiram significantly mitigates the effects of pennyroyal toxicity and does so more effectively than either agent alone. These data suggest that R-(+)-pulegone metabolism through CYP1A2 appears to be more important in the development of a hepatotoxic metabolite than does metabolism via CYP2E1.|Glutathione plays a role in the detoxication of pulegone. At hepatotoxic doses, pulegone depletes glutathione in the liver and the toxicity of pulegone on i.p. injection in mice is enhanced by treatment with diethyl maleate to decrease glutathione levels. No such increase in toxicity was seen with (R)-(+)-menthofuran . It was suggested that pulegone is analogous to acetaminophen in that saturation of the glutathione pathway leads to a higher proportion of the dose being metabolised to reactive metabolites (such as 8-pulegone aldehyde). However, in other studies, glutathione has been shown to react with menthofuran epoxide, the precursor to 8-pulegone aldehyde. Glutathione conjugation may play a major role in the detoxication of the reactive metabolite produced by cytochrome P450 ((R)-(+)-menthofuran or the gamma-ketoenal) as indicated by the isolation of glutathione conjugates, including a mixed glutathionyl glucuronide, from the bile of rats treated i.p. with pulegone. The evidencesuggests that the metabolic activation of pulegone occurring in animals also occurs in humans, resulting in the formation of (R)-(+)-menthofuran. At high concentrations, (R)-(+)-menthofuran is a proximate hepatoxic product but if the concentration of metabolites of pulegone is not sufficient to deplete hepatocellular concentrations of glutathione, hepatotoxicity may not be observed.|The role of cytochrome P450s in metabolic activation of (R)-(+)-pulegone has been demonstrated by the observations that a variety of P450-inhibitors decreased the toxicity while pretreatment with phenobarbital enhanced the toxicity of (R)-(+)-pulegone and (R)-(+)- menthofuran. Thus, oxidation appears to enhance the toxicity of (R)-(+)-pulegone and (R)-(+)-menthofuran, which is consistent with the fact that (R)-(+)-pulegone is converted to (R)-(+)-menthofuran via 9-hydroxypulegenone, and the reactive 8-pulegone aldehyde is an ultimate toxicant. Evidence that pulegone is oxidized to 9-hydroxypulegone via a free radical mechanism is provided from the observation that treatment with the free radical scavenger C-phyocyanin decreased the hepatotoxicity of pulegone in rats.

ingestion of greater than 15 mL (ca. 250 mg/kg bw for a 60 kg woman) resulted in death.

LD50 Rats (Wistar, male) i.p. 819 mg/kg (24 hr)/Peppermint Oil USP/|LD50 Rats oral 470 mg/kg /R-(+)-pulegone/|LD50 Rats ip 150 mg/kg|LD50 Dogs iv 330 mg/kg|LD50 Mice sc 1,709 mg/kg

GENETIC TOXICOLOGY Pulegone was tested in three independent bacterial mutagenicity assays. Results from two of the assays were negative, with and without exogenous metabolic activation enzymes (S9). One of these assays used the same lot of pulegone that was tested in the 2-year rodent bioassay. Bacterial strains tested in these two assays included S. typhimurium strains TA97, TA98, TA100, and TA1535 as well as E. coli strain WP2 uvrA/pKM101. Results of the third test, also conducted with the same lot of pulegone as the 2-year bioassay, were clearly positive in Salmonella typhimurium strain TA98 and in Escherichia coli strain WP2 uvrA/pKM101 in the presence of rat liver S9. In vivo, no significant increases in the frequencies of micronucleated erythrocytes were seen in peripheral blood of male or female mice in the 3-month study.|2-YEAR STUDY IN MICE Groups of 50 male and 50 female mice were administered 0, 37.5, 75, or 150 mg pulegone/kg body weight in corn oil by gavage, 5 days per week for 105 weeks. Survival of all dosed groups was similar to that of the vehicle controls. Mean body weights of 150 mg/kg males and females were less than those of the vehicle controls after weeks 25 and 33, respectively. The incidences of multiple hepatocellular adenoma were significantly increased in all dosed groups of males, and the incidences of hepatocellular adenoma (includes multiple) and hepatoblastoma (includes multiple) were significantly increased in the 75 mg/kg males. The combined incidences of hepatocellular adenoma, hepatocellular carcinoma, or hepatoblastoma occurred with positive trends and were significantly increased in 75 mg/kg males and 150 mg/kg females. The incidence of hepatocellular adenoma was significantly increased in 150 mg/kg females. The incidences of several non-neoplastic liver lesions were significantly increased, primarily in the 75 and 150 mg/kg groups. These non-neoplastic lesions included clear cell, eosinophilic, and mixed cell foci; focal fatty change; centrilobular hepatocyte hypertrophy; intravascular hepatocyte; necrosis; pigmentation; bile duct cyst and hyperplasia; and oval cell hyperplasia. In the kidney, incidences of hyaline glomerulopathy were significantly increased in all dosed groups of males and 75 and 150 mg/kg females. The incidence of mineralization was significantly increased in 150 mg/kg females, and the incidence of nephropathy in 150 mg/kg females and severity of nephropathy in 150 mg/kg males were increased. Incidences of congestion of the glomerulus were increased in 150 mg/kg males and females. The incidence of osteoma or osteosarcoma (combined) in all organs of 75 mg/kg females exceeded the historical control ranges. One 150 mg/kg male and one 75 mg/kg female had nasal osteoma; no nasal osteomas have been observed in historical control mice. The incidences of olfactory epithelial degeneration of the nose were significantly increased in all dosed groups of females and in 75 and 150 mg/kg males. Incidences of inflammation, nerve atrophy, and olfactory epithelium metaplasia of the nose were significantly greater in 150 mg/kg males and females than in the vehicle control groups. In the forestomach, incidences of squamous hyperplasia and inflammation were significantly increased in 75 mg/kg males and 150 mg/kg males and females, and the incidences of ulcer were significantly increased in 75 and 150 mg/kg males.|2-YEAR STUDY IN RATS Groups of 50 male and 50 female rats were administered 0, 18.75 (males only), 37.5, 75, or 150 (females only) mg pulegone/kg body weight in corn oil by gavage, 5 days per week for up to 104 weeks. Due to excessive morbidity and mortality, 75 mg/kg males and 150 mg/kg females were not administered pulegone after week 60 (stop-exposure); these groups were administered the corn oil vehicle until the end of the study. Survival of 37.5 mg/kg males was significantly less than that of the vehicle controls; only two 75 mg/kg stop-exposure males survived, and no 150 mg/kg stop-exposure females survived to the end of the study. Compared to those of the vehicle controls, mean body weights were less in 75 mg/kg stop-exposure males after week 13 and in 75 mg/kg and 150 mg/kg stop-exposure females after weeks 21 and 9, respectively. Clinical findings included thinness, lethargy, and ruffled fur in the 75 mg/kg stop-exposure males and 150 mg/kg stop-exposure females. The incidences of urinary bladder papilloma and of papilloma or carcinoma (combined) were significantly increased in 150 mg/kg stop-exposure females. In the kidney, incidences of hyaline glomerulopathy were significantly increased in 37.5 mg/kg and 75 mg/kg stop-exposure males and in all dosed groups of females. The severity of chronic progressive nephropathy was increased in 37.5 mg/kg and 75 mg/kg stop-exposure males and in 75 mg/kg and 150 mg/kg stop-exposure females; the incidences of nephropathy were significantly increased in 75 mg/kg and 150 mg/kg stop-exposure females. The incidence of renal cyst was significantly increased in 75 mg/kg stop-exposure males. In the liver, incidences of diffuse hepatocyte cellular alteration were significantly increased in 37.5 mg/kg and 75 mg/kg stop-exposure males and 75 mg/kg and 150 mg/kg stop-exposure females. There were significant increases in the incidences of other liver lesions including fatty change, bile duct cyst, hepatocyte necrosis, oval cell hyperplasia, bile duct hyperplasia, and portal fibrosis. In the nose, 37.5 mg/kg and 75 mg/kg stop-exposuremales and all dosed groups of females had significantly increased incidences of olfactory epithelium degeneration. All dosed groups of females had significantly increased incidences of respiratory metaplasia of the olfactory epithelium and nasal inflammation. In the forestomach, incidences of inflammation and ulcer were significantly increased in 37.5 mg/kg and 75 mg/kg stop-exposure males, and incidences of epithelial hyperplasia and perforation were increased in 75 mg/kg stop-exposure males. In the glandular stomach, the incidence of inflammation was significantly increased in 75 mg/kg stop-exposure males.|3-MONTH STUDY IN MICE Groups of 10 male and 10 female mice were administered 0, 9.375, 18.75, 37.5, 75, or 150 mg pulegone/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. All mice survived to the end of the study. Mean body weights of dosed mice were similar to those of the vehicle controls. Reduced and oxidized glutathione levels were generally greater than vehicle control levels in 150 mg/kg males and in 75 and 150 mg/kg females. Liver weights of 150 mg/kg males and 75 and 150 mg/kg females were significantly greater than those of the vehicle controls. No histopathologic lesions were observed that could be attributed to the administration of pulegone.|For more National Toxicology Program Studies (Complete) data for Pulegone (8 total), please visit the HSDB record page.

Pulegone is found in oils derived from plants of the Labiarae (mint) family as (+)-form(1). It is readily isolated in quantity from the pennyroyal oils from Mentha pulegium, M. Longifolia, and Hedeoma pulegioides(1,2). Pugelone is one of the components of the essential oil derived from Ziziphora clinopodioides, Blue Mint Bush or kakuti-e kuhi, (Labiarae (Lamiaceae)), which grows in Iran, Iraq, and parts of Turkey(3,4).

Pulegone's production and use as a chemical intermediate, flavoring(1) and herbal medication(2) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 670(SRC), determined from a log Kow of 3.08(2) and a regression-derived equation(3), indicates that pulegone is expected to have moderate mobility in soil(SRC). Volatilization of pulegone from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of 5.9X10-5 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Pulegone is expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 0.12 mm Hg at 25 °C(SRC), determined from a fragment constant method(3). Biodegradation data in soil were not available(SRC, 2013).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 670(SRC), determined from a log Kow of 3.08(2) and a regression-derived equation(3), indicates that pulegone is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(4) based upon an estimated Henry's Law constant of 5.9X10-5 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 22 hours and 10 days, respectively(SRC). According to a classification scheme(5), an estimated BCF of 50(SRC), from its log Kow(2) and a regression-derived equation(3), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Biodegradation data in water were not available(SRC, 2013).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), pulegone, which has an estimated vapor pressure of 0.12 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 pulegone 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 0.1 days(SRC), calculated from its rate constant of 1.1X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Pulegone contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

The rate constant for the vapor-phase reaction of pulegone with photochemically-produced hydroxyl radicals has been estimated as 1.12X10-10 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 0.1 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). The rate constant for the vapor-phase reaction of pulegone with ozone has been estimated as 4.8X10-16 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(1). This corresponds to an atmospheric half-life of about 0.02 days at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(2). Pulegone is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(3). Pulegone does contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 50 was calculated in fish for pulegone(SRC), using a log Kow of 3.08(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is moderate(SRC).

The Koc of pulegone is estimated as 670(SRC), using a log Kow of 670(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that pulegone is expected to have low mobility in soil.

The Henry's Law constant for pulegone is estimated as 5.9X10-5 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that pulegone 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 22 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 10 days(SRC). Pulegone's Henry's Law constant indicates that volatilization from moist soil surfaces may occur(SRC). Pulegone is expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 0.123 mm Hg(SRC), determined from a fragment constant method(3).

Pulegone concentrations in plants(1).|Pulegone, detected, not quantified in plants(1).[Table#8121]

The therapeutic indications for peppermint oil and mint oil are mainly related to common cold and gastrointestinal disturbances and presumably the vast majority of these products are used in selfmedication. An underreporting of side effects may be suspected.

A review of cases of human intoxication with pennyroyal oil (Mentha pulegium: pulegone content 62-97%) indicate that ...ingestion of greater than 15 mL (ca. 250 mg/kg bw for a 60 kg woman) resulted in death.

(R)-(+)-Pulegone, a monoterpene ketone, is a major component of pennyroyal oil. Ingestion of high doses of pennyroyal oil has caused severe toxicity and occasionally death. Studies have shown that metabolites of pulegone were responsible for the toxicity. Previous metabolism studies have used high, near lethal doses and isolation and analysis techniques that may cause degradation of some metabolites. To clarify these issues and further explore the metabolic pathways, a study of (14)C-labeled pulegone in F344 rats at doses from 0.8 to 80 mg/kg has been conducted. High-pressure liquid chromatography (HPLC) analysis of the collected urine showed the metabolism of pulegone to be extensive and complex. Fourteen metabolites were isolated by HPLC and characterized by NMR, UV, and mass spectroscopy. The results demonstrated that pulegone was metabolized by three major pathways: 1) hydroxylation to give monohydroxylated pulegones, followed by glucuronidation or further metabolism; 2) reduction of the carbon-carbon double bond to give diastereomeric menthone/isomenthone, followed by hydroxylation and glucuronidation; and 3) Michael addition of glutathione to pulegone, followed by further metabolism to give diastereomeric 8-(N-acetylcystein-S-yl)menthone/isomenthone. This 1,4-addition not only took place in vivo but also in vitro under catalysis of glutathione S-transferase or mild base. Several hydroxylated products of the two mercapturic acids were also observed. Contrary to the previous study, all but one of the major metabolites characterized in the present study are phase II metabolites, and most of the metabolites in free forms are structurally different from those previously identified phase I metabolites.|Pulegone, a monoterpene that protects source plants against predators, is a hepatotoxic constituent of the folklore abortifacient pennyroyal oil. In the rat, pulegone extensively depleted glutathione measured in both liver tissue and plasma, and its toxicity was markedly enhanced in animals treated with buthionine sulfoximine. The glutathione-depleting effect of pulegone was compromised following inhibition of cytochrome P-450 by piperonyl butoxide. In addition, /the authors/ found no evidence for conjugation of glutathione to unchanged pulegone in vitro. Administration of menthofuran, a known oxidative and hepatotoxic metabolite of pulegone, only marginally affected glutathione levels in plasma and liver, and toxicity was not augmented by buthionine sulfoximine. These results provide indirect evidence for cytochrome P-450-catalyzed bioactivation of pulegone via at least two independent pathways: 1) the formation and subsequent activation of menthofuran from pulegone; and 2) the formation of reactive intermediate(s) from pulegone, but not menthofuran, which can be detoxified through a mechanism requiring reduced glutathione.|(R)-(+)-Pulegone, a monoterpene constituent of pennyroyal oil, is a hepatotoxin that has been used in folklore medicine as an abortifacient despite its potential lethal effects. Pulegone is metabolized by human liver cytochrome P-450s to menthofuran, a proximate hepatotoxic metabolite of pulegone. Expressed human liver cytochrome (CYP) P-450s (1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4) were tested for their ability to catalyze the oxidations of pulegone and menthofuran. Expressed CYP2E1, CYP1A2, and CYP2C19 oxidized pulegone to menthofuran, with respective Km and Vmax values of 29 uM and 8.4 nmol/min/nmol P-450 for CYP2E1, 94 uM and 2.4 nmol/min/nmol P-450 for CYP1A2, and 31 uM and 1.5 nmol/min/nmol P-450 for CYP2C19. The human liver P-450s involved in the metabolism of menthofuran are the same as pulegone except for the addition of CYP2A6. These P-450s were found to oxidize menthofuran to a newly identified metabolite, 2-hydroxymenthofuran, which is an intermediate in the formation of the known metabolites mintlactone and isomintlactone. Based on studies with (18)O2 and H2(18)O, 2-hydroxymenthofuran arises predominantly from a dihydrodiol formed from a furan epoxide. CYP2E1, CYP1A2, and CYP2C19 oxidized menthofuran with respective Km and Vmax values of 33 uM and 0.43 nmol/min/nmol P-450 for CYP2E1, 57 uM and 0.29 nmol/min/nmol P-450 for CYP1A2, and 62 uM and 0.26 nmol/min/nmol P-450 for CYP2C19.|The major in vivo metabolites of (S)-(-)-pulegone in humans using a metabolism of ingestion-correlated amounts (MICA) experiment were newly identified as 2-(2-hydroxy-1-methylethyl)-5-methylcyclohexanone (8-hydroxymenthone, M1), 3-hydroxy-3-methyl-6-(1-methylethyl)cyclohexanone (1-hydroxymenthone, M2), 3-methyl-6-(1-methylethyl)cyclohexanol (menthol), and E-2-(2-hydroxy-1-methylethylidene)-5-methylcyclohexanone (10-hydroxypulegone, M4) on the basis of mass spectrometric analysis in combination with syntheses and NMR experiments. Minor metabolites were be identified as 3-methyl-6-(1-methylethyl)-2-cyclohexenone (piperitone, M5) and alpha,alpha,4-trimethyl-1-cyclohexene-1-methanol (3-p-menthen-8-ol, M6). Menthofuran was not a major metabolite of pulegone and is most probably an artifact formed during workup from known (M4) and/or unknown precursors. The differences in toxicity between (S)-(-)- and (R)-(+)-pulegone can be explained by the strongly diminished ability for enzymatic reduction of the double bond in (R)-(+)-pulegone. This might lead to further oxidative metabolism of 10-hydroxypulegone (M4) and the formation of further currently undetected metabolites that might account for the observed hepatotoxic and pneumotoxic activity in humans.|For more Metabolism/Metabolites (Complete) data for Pulegone (25 total), please visit the HSDB record page.

In rats pulegone (300 mg i.p.) caused dilation of the central veins and distension of sinusoidal spaces within 6 hours and centrilobular necrosis was observable starting at 12 hours. Electron microscopy after 24 hours showed degeneration of endoplasmic reticulum, swelling of mitochondria and nuclear changes. It has been suggested that metabolites of (R)-(+)-pulegone deactivate cytochrome P450s by modifying the prosthetic hem group or the apoprotein . In human liver microsomes in vitro, (R)-(+)-menthofuran specifically inhibits CYP2A6 and adducts with this enzyme have been isolated. CYP1A2, CYP2D6, CYP2E1 or CYP3A4 were not similarly inactivated.|(R)-(+)-Pulegone and its metabolite, (R)-(+)-menthofuran, are hepatotoxic and produce similar effects following i.p. injection in mice. These effects are similar to those reported following human intoxication with pennyroyal oil.

The cases are presented of 3 adult women and a 22-month-old girl who experienced adverse effects following ingestion of pennyroyal (Mentha pulegium); the findings were placed in the context of previously reported cases of pennyroyal toxicity. One of the adult patients died after acute ingestion of pennyroyal. The infant was treated with gastric lavage within 30 min of ingestion, followed by 1 g/kg activated charcoal and 2 mL/kg sorbitol. She was then given 190 mg/kg oral acetylcysteine (N-acetylcysteine) followed by 70 mg/kg every 4 hr for a total of 17 doses. The other 2 patients ingested minimally toxic amounts of pennyroyal and recovered without receiving acetylcysteine. In the fatal case, a serum sample obtained 72 hr after acute ingestion contained 18 ng/mL pulegone and 1 ng/mL menthofuran. In a serum sample from the patient treated with acetylcysteine, obtained 10 hr after ingestion, the menthofuran level was 40 ng/mL.|/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|For more Antidote and Emergency Treatment (Complete) data for Pulegone (8 total), please visit the HSDB record page.

/SIGNS AND SYMPTOMS/ A review of cases of human intoxication with pennyroyal oil (Mentha pulegium: pulegone content 62-97%) indicate that ingestion of 10 mL resulted in moderate to severe toxicity and ingestion of greater than 15 mL (ca. 250 mg/kg bw for a 60 kg woman) resulted in death. The clinical pathology is characterised by massive centrilobular necrosis, pulmonary edema and internal hemorrhage.|/CASE REPORTS/ A review of published reports of pennyroyal poisoning (1869 to 1996) identified 18 cases in which there was moderate to severe toxicity from ingestion of at least 10 mL (about 2 tsp.) of pennyroyal oil. The toxic symptoms included coma, seizures, and hepatic and renal effects. Ingestion of less than 10 mL was generally associated with gastritis and mild central nervous system toxicity. However, the severity of the toxic effects was not always related strictly to dose and depended on the use of emetics or other treatments. In two cases reported before 1905, coma and seizures were associated with ingestion of 5 mL pennyroyal oil; two other cases reportedly survived after ingestion of 30 mL. Variability in the toxic effects of pennyroyal oil may be due to differing concentrations of pulegone contained in preparations from European and American pennyroyal.|/CASE REPORTS/ The cases of 2 infants, an 8-wk-old boy and a 6-month-old boy, who developed hepatic and neurologic injury after ingestion of mint tea that contained the toxic agent pennyroyal oil are reported. Fulminant liver failure with cerebral edema and necrosis developed in the first infant, who died. This infant was positive only for menthofuran (10 ng/mL), a metabolite of a toxic constituent (pulegone) of pennyroyal oil. In the other infant, who was positive for both pulegone (25 ng/mL) and menthofuran (41 ng/mL), hepatic dysfunction and a severe epileptic encephalopathy developed. When he was discharged 2 months after admission his hepatocellular enzyme markers remained elevated.|/CASE REPORTS/ Pennyroyal is a widely available herb that has long been used as an abortifacient despite its potentially lethal hepatotoxic effects. However, quantitative data for pennyroyal constituents and their metabolites in humans have not been previously reported. We report four cases of pennyroyal ingestion. One patient died, one received N-acetylcysteine, and two ingested minimally toxic amounts of pennyroyal and were not treated with N-acetylcysteine. In the fatal case, postmortem examination of a serum sample, which had been obtained 72 hours after the acute ingestion, identified 18 ng of pulegone per mL and 1 ng of menthofuran per mL. In a serum sample from the patient treated with N-acetylcysteine, which had been obtained 10 hours after ingestion, the menthofuran level was 40 ng/mL. Review of 18 previous case reports of pennyroyal ingestion documented moderate to severe toxicity in patients who had been exposed to at least 10 mL of pennyroyal oil. Pennyroyal continues to be an herbal toxin of public health importance. Data on human metabolites may provide new insights into the toxic mechanisms and treatment of pennyroyal poisoning, including the potential role of N-acetylcysteine. Better understanding of the toxicity of pennyroyal may also lead to stricter control of and more restricted access to the herb.|For more Human Toxicity Excerpts (Complete) data for Pulegone (7 total), please visit the HSDB record page.

cis-isopulegone

Cyclohexanone, 5-methyl-2-(1-methylethylidene)-, (5R)-: ACTIVE|(R)-(+)-pulegone, together with (R)-(+)-menthofuran, is a constituent of peppermint oil and pennyroyal oil and occurs naturally at lower levels in other foods such as oregano, beans and tea. (S)-(-)-pulegone is contained in Buchu leaf oil, a steam distillate from Agathosma betulina which is used as a source for flavorings imparting "cassis" type aromas.|Peppermint oil contains maximum 4.0 % pulegone and between 1.0 and 9.0 % menthofuran. Mint oil, partly dementholised contains maximum 2.0 % pulegone, but no limit is given for menthofuran. There is no Ph Eur monograph on pennyroyal or pennyroyal oil. It is known from the literature that pennyroyal herb contains 1-2% essential oil of which pulegone is the principal component (60-90%).|Pulegone is found in young peppermint leaves, and is metabolized to menthol as the leaves mature.|Monoterpenes, such as pulegone, may be potential environmentally safe substitutes for traditional pesticides.|Naturally occuring plant constituents are potentially useful as avian feeding deterrents. In a series of cage trials, pulegone, a compound found in various species of mint, suppressed consumption of rice seed by red-winged blackbirds (Agelaius phoeniceus) more effectively than methyl anthranilate. Furthermore, pennyroyal oil, from which pulegone is obtained, was nearly as effective as pulegone itself. Brown-headed cowbirds (Molothrus ater) were more sensitive to pulegone than were redwings, but female boat-tailed grackles (quiscalus major) were less sensitive. Because pulegone produces both sensory irritation and post-ingestive distress, it has potential for seed treatment and other bird deterrent applications. /Experimental use/

Flavoring Agents -> JECFA Flavorings Index|Lipids -> Prenol Lipids [PR] -> Isoprenoids [PR01] -> C10 isoprenoids (monoterpenes) [PR0102]

Flavoring Agents