4-Hydroxy-2,5-dimethylfuran-2(3H)-on

Relatively weak, nonspecific odor; dilute solutions develop a pineapple, strawberry-like odor

Odor description at 0.01%: Sweet, slightly burnt brown caramellic, cotton candy with a savory nuance

Caramel flavor

Taste description at 0.10-1.00 ppm: Sweet caramellic cooked meaty and fruity nuances

Beige powder

Colorless crystals

In water, 0.315 g/mL at 25 °C

Soluble in oil and ethanol

Soluble in oil; Insoluble in water

Soluble (in ethanol)

77-79 °C

77 - 78 °C

Liquid

Solid

Colourless to white solid; Fruity caramel or burnt pineapple aroma

This chemical does not meet GHS hazard criteria for < 0.1% (1 of 1843) of reports.

Warning

H302 (28.5%): Harmful if swallowed [Warning Acute toxicity, oral]；H317 (80.1%): May cause an allergic skin reaction [Warning Sensitization, Skin]；H319 (71.7%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]

P261, P264, P264+P265, P270, P272, P280, P301+P317, P302+P352, P305+P351+P338, P321, P330, P333+P317, P337+P317, P362+P364, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 1843 reports by companies from 16 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.；Reported as not meeting GHS hazard criteria per 1 of 1843 reports by companies.；There are 15 notifications provided by 1842 of 1843 reports by companies with hazard statement code(s).；Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website.

Chemical: 3(2H)-Furanone, 4-hydroxy-2,5-dimethyl-

Commission Regulation (EC) No 1565/2000 (Repealed by Com. Implementing Reg. (EU) No 872/2012)

3(2H)-Furanone, 4-hydroxy-2,5-dimethyl- is listed on the EPA's Chemical Data Reporting (CDR) system. Manufacturers and importers of 3(2H)-Furanone, 4-hydroxy-2,5-dimethyl- are required to report information about their production and use of this chemical to the EPA under the Toxic Substances Control Act (TSCA). (40 eCFR Part 711)

Status: Active Update: 20-12-2019 https://echa.europa.eu/registration-dossier/-/registered-dossier/22015

3(2H)-Furanone, 4-hydroxy-2,5-dimethyl-: Does not have an individual approval but may be used under an appropriate group standard

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

SRP: Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in air, soil or water; effects on animal, aquatic and plant life; and conformance with environmental and public health regulations. If it is possible or reasonable use an alternative chemical product with less inherent propensity for occupational harm/injury/toxicity or environmental contamination.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company; Contaminated packaging: Dispose of as unused product.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust. Environmental precautions: Do not let product enter drains.

Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Further processing of solid materials may result in the formation of combustible dusts. The potential for combustible dust formation should be taken into consideration before additional processing occurs. Provide appropriate exhaust ventilation at places where dust is formed.

Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

Skin protection: Handle with gloves.

Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.

Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator. For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

2,5-Dimethyl-4-hydroxy-3(2 H)-furanone (DMHF), produced by Maillard reaction of sugar/amino acid and found in various foodstuffs, showed mutagenicity to Salmonella typhimurium TA100 strain with and without S9 mix, and induced micronucleated mouse peripheral reticulocytes. DNA strand breaking activity of the compound at pH 7.4 increased with the increasing dose of the compound and with the increasing incubation time. The breaking activity was inhibited in the presence of superoxide dismutase, catalase, hydroxyl radical scavengers, spin trapping agents, thiol compounds and metal chelators, and also by removal of dissolved oxygen from the incubation mixture. Addition of Fe(III) ion to the incubation mixture enhanced the breaking activity. Incubation of DMHF with 5,5-dimethyl-1-pyrroline N-oxide (DMPO) gave electron spin resonance signals characteristic to DMPO-OH adduct, indicating generation of hydroxyl radical. It was found that DMHF generated hydroxyl radical with an aid of a trace amount of metal ions, and induced DNA strand breaking. Mutagenicity and induction of micronucleated reticulocytes by DMHF may be caused as a result of DNA modification via hydroxyl radical.

Prooxidant properties of furanone compounds including 2,5-furanone (furaneol, 4-hydroxy-2,5-dimethyl-furan-3-one), 4,5-furanone (4,5-dimethyl-3-hydroxy-2(5H)-furanone) (sotolone) and cyclotene (2-hydroxy-3-methyl-2-cyclopenten-1-one) were analyzed in relation to the metal-reducing activity. Only 2,5-furanone known as a "strawberry or pineapple furanone" inactivated aconitase the most sensitive enzyme to active oxygen in the presence of ferrous sulfate, suggesting the furaneol/iron-mediated generation of reactive oxygen species. 2,5-Furanone caused strand scission of pBR322 DNA in the presence of copper. Treatment of calf thymus DNA with 2,5-furanone plus copper produced 8-hydroxy-2'-deoxyguanosine in DNA. 2,5-Furanone showed a potent copper-reducing activity, and thus, DNA strand breaks and the formation of 8-hydroxy-2'-deoxyguanosine by 2,5-furanone can be initiated by the production of superoxide radical through the reduction of cupric ion to cuprous ion, resulting in the conversion to hydrogen peroxide and hydroxyl radical. However, an isomer and analog of 2,5-furanone, 4,5-furanone and cyclotene, respectively, did not show an inactivation of aconitase, DNA injuries including strand breakage and the formation of 8-hydroxy-2'-deoxyguanosine, and copper-reducing activity. Cytotoxic effect of 2,5-furanone with hydroxyketone structure can be explained by its prooxidant properties: furaneol/transition metal complex generates reactive oxygen species causing the inactivation of aconitase and the formation of DNA base damage by hydroxyl radical.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1(SRC), determined from a structure estimation method(2), indicates that dimethylhydroxy furanone is expected to have very high mobility in soil(SRC). Volatilization of dimethylhydroxy furanone from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.5X10-5 atm-cu m/mole(SRC), using a fragment constant estimation method(2). Dimethylhydroxy furanone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 0.008 mm Hg at 25 °C(SRC), determined from a fragment constant method(2); however, dimethylhydroxy furanone does emit an odor(3) even though it exists as a solid. Biodegradation data in soil were not available(SRC, 2016).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1(SRC), determined from a structure estimation method(2), indicates that dimethylhydroxy furanone is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon an estimated Henry's Law constant of 1.5X10-5 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 3 and 25 days, respectively(SRC). According to a classification scheme(4), an estimated BCF of 3(SRC), from its log Kow of 0.95(5) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions(3). Dimethylhydroxy furanone is an olefinic compound and olefins in surface waters exposed to sunlight react with photo-oxidants with a half-life on the order of 25 days(6).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), dimethylhydroxy furanone, which has an estimated vapor pressure of 0.008 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 dimethylhydroxy furanone 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 1.4X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). Vapor-phase dimethylhydroxy furanone is also degraded in the atmosphere by reaction with ozone(SRC); the half-life for this reaction in air is estimated to be 5 hours(SRC), calculated from its rate constant of 5.7X10-17 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). Dimethylhydroxy furanone contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Dimethylhydroxy furanone is a constituent of pineapple and strawberry aroma and is also found in other foods(1). Volatiles emitted from rice cakes from two commercial companies contained dimethylhydroxy furanone levels of 15 and 90 ppb respectively(2). Dimethylhydroxy furanone was detected in the volatiles of muskmelon fruit (C. melo L. Cv. Miyabi)(3). Dimethylhydroxy furanone was identified in volatiles from roasted chestnuts(4). The volatile compounds extracted from the red-skinned cultivar of rambutan, Jitlee (Nephelium lappaceum L.), a tropical fruit native to Southeast Asia, contained a dimethylhydroxy furanone concentration of 240.15 ug/L in the juice(5). Dimethylhydroxy furanone was detected in the aroma odorants from freshly prepared popcorn(6). It has been detected in both red and white wines(7). Dimethylhydroxy furanone is reported to occur in guava, grapes, pineapple, raspberry, staewberry fruit and jams, rye bread, Swiss cheese, boiled beef, beer, cocoa, coffee, tea, filberts, almonds, oatmeal, Arctic bramble, yellow passion fruit, mango, fermented soy sauce, malt and Cape gooseberry(8). Dimethylhydroxy furanone was detected in beef extract aroma(9) and in beer(10).

IDENTIFICATION AND USE: Dimethylhydroxy furanone is a beige powder. It is used as a flavoring agent and experimental medication. HUMAN EXPOSURE AND TOXICITY: 2,5-Dimethyl-4-hydroxy-3(2H)-furanone (2,5-DMHF), a caramel-like fragrant compound found in many processed foodstuffs, has been reported to be mutagenic. 2,5-DMHF generates superoxide and subsequently hydrogen peroxide to induce metal-dependent DNA damage. ANIMAL STUDIES: Groups of 60 male and 60 female rats were given diets containing 2,5-DMHF at a dose of 0 (control), 100, 200 or 400 mg/kg bw per day for 24 months. No significant compound-related effects were reported in any of the animals at 100 and 200 mg/kg bw per day. The mean body weights and body-weight gains of males and females at the highest dose (400 mg/kg bw per day) were significantly lower than those of control animals at 24 months. The mean survival rate for males in the group receiving the highest dose was significantly lower (approximately 20%, p<0.05) than that of males in the control group at 24 months. The authors concluded that this finding was attributable to an increased incidence of adenomas of the pars distalis of the pituitary, with subsequent compression of the hypothalamic region within the brains of males at the highest dose. It was concluded that these adenomas were common, spontaneous tumors that were unrelated to the administration of 2,5-DMHF. 2,5-DMHF showed mutagenicity to Salmonella typhimurium TA100 strain with and without metabolic activation, and induced micronucleated mouse peripheral reticulocytes. 2,5-DMHF induced micronucleated reticulocytes in mouse peripheral blood in a dose-dependent manner after oral administration /at doses of 0.5-1.0 g/kg/. The results indicate that DMHF can cause genetic damage after oral administration.

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. 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/[USEPA; ICSS Dashboard Application; Available from, as of July 7, 2016: http://actor.epa.gov/dashboard/]

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

Dimethylhydroxy furanone was first identified in pineapples in 1965 and has been isolated from many different fresh fruits such as strawberry, raspberry, tomato, kiwi, lychee, and snake fruit(1). Dimethylhydroxy furanone was detected in the sex pheromone of the wingless cockroach Eurycotis floridana (Polyzosteriinae)(2).

/GENOTOXICITY/ 2,5-Dimethyl-4-hydroxy-3(2H)-furanone (2,5-DMHF), a caramel-like fragrant compound found in many processed foodstuffs, has been reported to be mutagenic. 4,5-Dimethyl-3-hydroxy-2(5H)-furanone (4,5-DMHF), which is a similar characteristic fragrant compound, has no report concerning its mutagenicity. DNA damage by 2,5-DMHF and 4,5-DMHF was investigated by using DNA fragments obtained from the /human/ p53 tumor suppressor gene. 2,5-DMHF induced DNA damage extensively in the presence of Cu(II), but only slightly in the presence of Fe(III). 4,5-DMHF did not cause metal-dependent DNA damage. Bathocuproine, a Cu(I)-specific chelator, and catalase inhibited DNA damage induced by 2,5-DMHF plus Cu(II), whereas free hydroxyl radical scavengers did not. The order of DNA cleavage sites was thymine, cytosine>guanine residues. The site-specific DNA damage and effects of scavengers show that DNA-copper-oxygen complex rather than free *OH are involved in the DNA damage. Formation of 8-oxodeoxyguanosine (8-oxodG) by 2,5-DMHF increased with its concentration in the presence of Cu(II), whereas 8-oxodG formation increased only slightly in the presence of Fe(III). Degradation of 2,5-DMHF was efficiently accelerated by Cu(II), but only slightly accelerated by Fe(III). The degradation of 4,5-DMHF was little even in the presence of metal ions. Examination using cytochrome c suggests that superoxide was generated from 2,5-DMHF. Stoichiometric study of Cu(II) reduction revealed that autoxidation of 2,5-DMHF could offer 4-electron reduction. These results suggest that, at least in vitro and in an acellular system, 2,5-DMHF generates superoxide and subsequently hydrogen peroxide to induce metal-dependent DNA damage.

Chemical: 3(2H)-Furanone, 4-hydroxy-2,5-dimethyl-

Commission Regulation (EC) No 1565/2000 (Repealed by Com. Implementing Reg. (EU) No 872/2012)

3(2H)-Furanone, 4-hydroxy-2,5-dimethyl- is listed on the EPA's Chemical Data Reporting (CDR) system. Manufacturers and importers of 3(2H)-Furanone, 4-hydroxy-2,5-dimethyl- are required to report information about their production and use of this chemical to the EPA under the Toxic Substances Control Act (TSCA). (40 eCFR Part 711)

Status: Active Update: 20-12-2019 https://echa.europa.eu/registration-dossier/-/registered-dossier/22015

3(2H)-Furanone, 4-hydroxy-2,5-dimethyl-: Does not have an individual approval but may be used under an appropriate group standard

2,5-Dimethyl-4-hydroxy-3[2H]furanone (Furaneol, DMHF) [3658-77-3], an important flavor constituent of strawberry fruit, was administered to four male and two female volunteers using fresh strawberries as a natural DMHF source. The amount excreted was determined by measuring urinary levels of DMHF and DMHF glucuronide. DMHF glucuronide was synthesized and the structure elucidated by mens of (1)H, (13)C and two dimensional nuclear magnetic resonance, as well as mass spectral data. Identification and quantification of DMHF glucuronide in human urine were achieved after solid phase extraction on XAD-2 using reverse-phase reverse-phase HPLC with either on-line UV/VIS or electrospray tandem mass spectrometry detection. Male and female volunteers excreted 59-69% and 81-94%, respectively, of the DMHF dose (total of free and glycosidically bound DMHF in strawberries) as DMHF glucuronide in urine within 24 hr. The amount of DMHF excretion was independent of the dose size and the ratio of free to glycosidically bound forms of DMHF in strawberry fruit. DMHF, DMHF glucoside and its 6'-O-malonyl derivative, naturally occurring in strawberries, were not detected in human urine.

Fragrant hydroxyfuranone and dihydroxypyranone derivatives generated in the Maillard reaction of sugars and amino acids are detected in various processed foods and have been shown active to break DNA single-strand in the in vitro studies. In the present study, absorption of 2,5-dimethyl-4-hydroxy-3(2 H)-furanone (DMHF) and 4-hydroxy-2(or 5)-ethyl-5(or 2)-methyl-3(2 H)-furanone (HEMF), both found in soy sauce, into plasma after a single intraperitoneal or oral administration at doses of 0.5-1.0 g/kg to mice was examined. Both compounds appeared in plasma 15 min after intraperitoneal administration and disappeared 2 hr after the administration. They appeared in plasma 5 min after oral administration, reached maximum after 15-45 min, and gradually disappeared after 2 h, indicating that they are absorbed by the digestive tract. Both DMHF and HEMF induced micronucleated reticulocytes (MNRETs) in mouse peripheral blood in a dose-dependent manner after oral administration. The results indicate that DMHF and HEMF can cause genetic damage after oral administration.

4-Hydroxy-2,5-dimethyl-3(2H)-furanone is expected to share the same metabolic fate as the primary material, i.e. conjugation with glucuronic acid and excretion in the urine.

For 4-hydroxy-2,5-dimethyl-3-(2H)furanone (USEPA/OPP Pesticide Code: 127501) there are 0 labels match. /SRP: Not registered for current use in the U.S., but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./

Reported uses (ppm):；Table: Reported uses (ppm): (Flavor and Extract Manufacturers' Association, 1994) [Table#8337]

Flavoring of foods

Cigarette additive

MEDICATION

4-Hydroxy-2,5-dimethyl-3(2H)-furanone

3(2H)-Furanone, 4-hydroxy-2,5-dimethyl-; 2,5-Dimethyl-4-hydroxy-2,3-dihydrofuran-3-one; 4-Hydroxy-2,5-dimethylfuran-3(2H)-one; Dimethylhydroxy furanone; Strawberry furanone; Furaneol (Commercial name); Neofuraneol (Commercial name); Pineapple compound (Commercial name)

IFRA_STD_201.pdf

49

IFRA 51st Amendment - Guidance for the use of IFRA Standards

Restriction: This material should be used only in the limited quantity as stated in the Standard

From dimethyl-3,4-dihydroxyfuran-2,5-dicarboxylate.

... manufactured in a multistep bioprocess from rhamnose.

It is synthesized by the reaction of hex-3-yne-2,5-diol with ozone and subsequent reductive work-up. ... The hexane-2,5-diol-3,4-dione formed in the oxidation step is then cyclized in a separate step to form furaneol.

Fragrance Ingredients

Flavouring Agent -> FLAVOURING_AGENT -> JECFA Functional Classes

Flavoring Agents -> JECFA Flavorings Index

Cosmetics -> Tonic

0.045 [Products applied to the lips]

0.014 [Products applied to the axillae]

0.27 [Products applied to the face/body using fingertips]

0.25 [Products related to fine fragrances]

0.064 [Products applied to the body using the hands (palms), primarily leave-on (Body lotion)]

0.064 [Products applied to the face using the hands (palms), primarily leave-on (Face moisturizer)]