Diethyl fumarate

Insoluble in water; soluble in acetone and choloform

SLIGHTLY SOL IN WATER

0.17 [mmHg]

Vapor pressure: 1 mm Hg at 53.2 °C

This chemical does not meet GHS hazard criteria for 1.7% (6 of 351) of reports.

Warning

H302 (98%): Harmful if swallowed [Warning Acute toxicity, oral]

P260, P261, P264, P270, P271, P272, P280, P301+P317, P302+P352, P304+P340, P308+P316, P319, P321, P330, P332+P317, P333+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 351 reports by companies from 13 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Warning

Chemical: 2-Butenedioic acid, (E)-, diethyl ester

Commission Regulation (EC) No 1565/2000 (Repealed by Com.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

Diethyl fumarate: Does not have an individual approval but may be used under an appropriate group standard

Organization for Economic Cooperation and Development; Screening Information Data Set for 2-Butenedioic acid (E)- Diethyl ester , 623-91-6 (2002). Available from the Database Query page at: http://www.chem.unep.ch/irptc/sids/OECDSIDS/sidspub.html as of March 6, 2009.

1 - Materials that, under emergency conditions, can cause significant irritation.

1 - Materials that must be preheated before ignition can occur. Materials require considerable preheating, under all ambient temperature conditions, before ignition and combustion can occur.

0 - Materials that in themselves are normally stable, even under fire conditions.

Diethyl fumarate

D: Other compounds that may form peroxides

Kelly

Acute Tox. 4 (98%)

Acute toxicity (Oral) - Category 4

To fight fire, use alcohol foam, foam, CO2 dry chemical.

Special protective equipment for fire-fighters - Wear self contained breathing apparatus for fire fighting if necessary.

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

Accidental release measures. Personal precautions - Use personal protective equipment. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Environmental precautions - Do not let product enter drains. Methods for cleaning up - Soak up with inert absorbent material and dispose of as hazardous waste. Keep in suitable, closed containers for disposal.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

This combustible material may be burned in a chemical incinerator equipped with an afterburner and scrubber. Observe all federal, state, and local environmental regulations. Contact a licensed professional waste disposal service to dispose of this material.

SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place.

Hand protection - Handle with gloves. For prolonged or repeated contact use protective gloves. Eye protection - Safety glasses. Skin and body protection - Choose body protection according to the amount and concentration of the dangerous substance at the work place.

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

Avoid inhalation of vapor or mist. Keep away from sources of ignition - No smoking. Take measures to prevent the build up of electrostatic charge.

In case of skin contact, wash off with soap and plenty of water.

Where risk assessment shows air-purifying respirators are appropriate use a full-face respirator with multipurpose combination (US) or type ABEK (EN 14387) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

To investigate the mechanisms of non-immunologic contact urticaria (NICU), the effects of 1g + 1g of acetylsalicylic acid (ASA) on contact reactions to methyl nicotinate, diethyl fumarate, benzoic acid, cinnamic acid, cinnamic aldehyde and dimethyl sulfoxide were studied in 21 test subjects. Erythema and edema reactions were observed visually, and the changes in the skin blood flow were monitored using laser-Doppler flowmetry. ASA had a significant inhibitory effect on erythema from all 6 agents and also on edema from all substances except dimethyl sulfoxide. The mechanism of the effect may be a result of the inhibitory influence of ASA on prostaglandin bioformation. Thus, to avoid false negative test results, non-steroidal anti-inflammatory drugs should not be used during NICU tests.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 11(SRC), determined from a structure estimation method(2), indicates that diethyl fumarate is expected to have very high mobility in soil(SRC). Volatilization of diethyl fumarate from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.4X10-8 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Diethyl fumarate is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 0.18 mm Hg at 25 °C(SRC), determined from a fragment constant method(4). Biodegradation data were not available(SRC, 2009).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 11(SRC), determined from a structure estimation method(2), indicates that diethyl fumarate is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 2.4X10-8 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 10(SRC), from an estimated log Kow of 2.20(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Hydrolysis is expected to be an important environmental fate process based upon base-catalyzed second-order hydrolysis half-lives of 100 and 10 days at pH values of 7 and 8, respectively(8). Biodegradation data were not available(SRC, 2008).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), diethyl fumarate, which has an estimated vapor pressure of 0.18 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 diethyl fumarate 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 1.6 days(SRC), calculated from its rate constant of 1.0X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Diethyl fumarate contains chromophores that absorb at wavelengths >290 nm(4) and therefore may be susceptible to direct photolysis by sunlight(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of diethyl fumarate can be estimated to be 11(SRC). According to a classification scheme(2), this estimated Koc value suggests that diethyl fumarate is expected to have very high mobility in soil.

Diethyl fumarate was detected in air for up to 72 hours following aerial spraying of malathion in 1990 in California to control the Mediterranean fruit fly; it is a breakdown chemical of the pesticide(1). Concentrations in ng/cu m (time frame in hours) were: 0.7 (-24 to 0); 29.6 (during spray); 16.0 (post spray); 21.6 (24-28); 21.2 (48-72); 1.7 (96-120); and 1.0 (192-216)(1).

/HUMAN EXPOSURE STUDIES/ In 12 healthy volunteers the topical application of monoethyl fumarate caused a spontaneous persistent erythema. Systemic application induced flush. In urticaria pigmentosa the influence was significant higher than in normal skin. This fact suggests a mast cell degranulation caused by monoethyl fumarate. /Monoethyl fumarate/

/CASE REPORTS/ Allergic contact dermatitis from esters of fumaric acid or esters of maleic acid is rare. The case of a chemist with allergic reactions to esters both of fumaric acid and of maleic acid is presented. Extremely high sensitivity of the patient to diethyl fumarate was noted. The formation of identical complete antigens from esters of these two cis-trans isomeric acids may be an explanation of the patient's double allergy. This is discussed from a stereochemical point of view. These stereochemical considerations point to a general mechanism where cis-trans isomeric alpha,beta-unsaturated carbonyl compounds are converted into the same complete antigen.

/OTHER TOXICITY INFORMATION/ The contact urticariagenic properties of diethyl fumarate were studied using the guinea pig ear swelling assay and by open application on the human upper back skin. Diethyl fumarate caused non-immunologic contact urticaria in both human and guinea pig skin, and the reactions exhibited similar dose dependency and timing of maximal response.

Diethyl fumarate's production and use as a chemical modifier(1) may result in its release to the environment through various waste streams(SRC). Its presence as an impurity of the pesticide malathion(1) will result in its direct release to the environment upon application of the parent pesticide(SRC).

An estimated BCF of 10 was calculated in fish for diethyl fumarate(SRC), using an estimated log Kow of 2.2(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Henry's Law constant for diethyl fumarate is estimated as 2.4X10-8 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that diethyl fumarate is expected to be essentially nonvolatile from water surfaces(2). Diethyl fumarate's Henry's Law constant indicates that volatilization from moist soil surfaces may not occur(SRC). Diethyl fumarate is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 0.18 mm Hg(SRC), determined from a fragment constant method(3).

/LABORATORY ANIMALS: Acute Exposure/ The decrease in the swelling capacity and the length of the refractory period after nonimmunologic contact urticaria produced by one application of six human nonimmunologic contact urticaria agents was studied with the use of the guinea pig ear test. On retesting 1 day later, all substances (benzoic acid, cinnamic acid, cinnamic aldehyde, diethyl fumarate, methyl nicotinate, and dimethyl sulfoxide) showed reactions decreased by at least 50%. ... The tachyphylaxis was not specific to the substance producing it; reactivity to other contact urticaria agents decreased as well. The refractory period was 4 days after methyl nicotinate, 8 days after diethyl fumarate and cinnamic aldehyde, and 16 days after the other agents...

/LABORATORY ANIMALS: Acute Exposure/ The contact urticariagenic properties of diethyl fumarate were studied using the guinea pig ear swelling assay and by open application on the human upper back skin. Diethyl fumarate caused non-immunologic contact urticaria in both human and guinea pig skin, and the reactions exhibited similar dose dependency and timing of maximal response.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Male and female SD rats were orally administered (gavage) at doses of 0, 11, 30 and 100 mg/kg/day. In male rats, the administration period was two weeks prior to mating, 2 weeks of mating and 2 weeks after the completion of mating period. In female, in addition to maximum four weeks pre-mating and mating period, they were given through pregnant period until day 3 of post delivery. Histopathological examination of the forestomach revealed thickening of the mucosal layer in both sexes of all treated groups, hyperkeratosis in males of all treated groups and in females of the 30 and 100 mg/kg groups. These changes were dose-dependent. In addition, edema in the submucosal tissue as well as ulcer and focal edema in lamina propria mucosae were noted in males and females of the 30 mg/kg groups, and vesiculation in the superficial zone of the mucosal layer was apparent in males of the 30 and 100 mg/kg groups. Absolute or relative organ weights of the kidney and liver increased in both sexes of the 100 mg/kg groups, and atrophy of the thymus was noted in females of the 30 and 100 mg/kg groups. No effects were observed on clinical signs, body weight, food consumption, urinalysis. NOEL was considered to be less than 11 mg/kg/day.

/GENOTOXICITY/ Diethyl fumarate showed negative results in Salmonella typhimurium TA100, TA1535, TA98, TA1537 and Escherichia coli WP2 uvrA at concentrations up to 5 mg/plate with or without metabolic activation system.

/GENOTOXICITY/ A chromosomal aberration test ... was conducted using cultured Chinese hamster lung (CHL/IU) cells. ... The maximum concentration of the chemical was used with no apparent cytotoxic effect in continuous treatment. In short term treatment, it was set to 0.083 mg/mL. Although chromosomal aberrations were not recognized up to a maximum concentration of 0.083 mg/mL under conditions of both continuous treatment and short-term treatment with an exogenous metabolic activation system, a positive result was obtained without metabolic activation.

The rate constant for the vapor-phase reaction of diethyl fumarate with photochemically-produced hydroxyl radicals has been estimated as 1X10-11 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 1.6 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). The rate constant for the vapor-phase reaction of diethyl fumarate with ozone has been estimated as 0.17X10-12 cu cm/molecule-sec at 25 °C(SRC) that were derived using a structure estimation method(1). This corresponds to an atmospheric half-life of about 6 days at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(2). A base-catalyzed second-order hydrolysis rate constant of 0.77 L/mole-sec(SRC) was estimated using a structure estimation method(3); this corresponds to half-lives of 100 and 10 days at pH values of 7 and 8, respectively(3). Diethyl fumarate contains chromophores that absorb at wavelengths >290 nm(4) and therefore may be susceptible to direct photolysis by sunlight(SRC).

Occupational exposure to diethyl fumarate may occur through inhalation of dust and dermal contact with this compound at workplaces where diethyl fumarate is produced or used. Limited monitoring data indicate that the general population may be exposed to diethyl fumarate via inhalation of air in areas immediately following the aerial application of malathion. (SRC)

Used as a co-monomer to make polymers; [HSDB]

COMONOMER FOR POLYMERS, EG, WITH STYRENE & VINYL CHLORIDE

As a chemical modifier

It is used as a ... comonomer for production of polystyrene.

(1979) No Data

(1981) No Data

(1979) No Data

(1981) No Data

(1979) NO EVIDENCE OF COMMERCIAL PRODN IN U.S.

(1981) NO EVIDENCE OF COMMERCIAL PRODN IN U.S.

2-Butenedioic acid (2E)-, diethyl ester is listed as a High Production Volume (HPV) chemical (65FR81686). Chemicals listed as HPV were produced in or imported into the U.S. in >1 million pounds in 1990 and/or 1994. The HPV list is based on the 1990 Inventory Update Rule. (IUR) (40 CFR part 710 subpart B; 51FR21438).

Production volumes for non-confidential chemicals reported under the Inventory Update Rule. [Table#5523]

2-Butenedioic acid (2E)-, 1,4-diethyl ester: ACTIVE

Diethyl fumarate is an impurity in malathion