(4-Ethoxyphenyl)urea

180.207

180.20

205-767-7

8U78KF577Z

1839

DTXSID9020580

White needle-like crystals or powder|Lustrous needles|Leafs (from dilute alcohol), plates (from water)

2924299090

64.4

1.28 (est)

Dulcin appears as white crystals. (NTP, 1992)

1.199

173.5 °C

Decomposes

134.6ºC

1.5373 (estimate)

1.21 mg/mL at 21 °C

0-6ºC

9.8X10-6 mm Hg at 25 deg C (est)

Very sweet taste, about 250 times as sweet as sugar cane

Henry's Law constant = 1.58X10-11 atm-cu m/mol at 25 °C (est)

Partially decomposes on heating with water; hydrolyzes in N acetic acid|Hydroxyl radical reaction rate constant = 4.4X10-11 cu cm/molecule-sec at 25 °C (est)

Partially decomposes on heating in water; hydrolyzes in 0.1 N acetic acid. Slightly water soluble (NTP, 1992).

Amides and Imides

Water-Reactive

DULCIN is an example of an amide. Amides react with azo and diazo compounds to generate toxic gases. Flammable gases are formed by the reaction of organic amides with strong reducing agents. Amides are very weak bases (weaker than water). Imides are less basic yet and in fact react with strong bases to form salts. That is, they can react as acids. Mixing amides with dehydrating agents such as P2O5 or SOCl2 generates the corresponding nitrile. The combustion of these compounds generates mixed oxides of nitrogen (NOx).

Xi

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational harm/injury/toxicity or environmental contamination. 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 soil or water; effects on animal and plant life; and conformance with environmental and public health regulations.

Substances generally prohibited from direct addition or use as human food. ... Food containing any added or detectable level of dulcin is deemed to be adulterated in violation of the act, based upon an order published in the Federal Register of January 19, 1950 (15 FR 321).

SMALL SPILLS AND LEAKAGE: Should a spill occur while you are handling this chemical, FIRST REMOVE ALL SOURCES OF IGNITION, then you should dampen the solid spill material with ethanol and transfer the dampened material to a suitable container. Use absorbent paper dampened with ethanol to pick up any remaining material. Seal the absorbent paper, and any of your clothes, which may be contaminated, in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with ethanol followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned. STORAGE PRECAUTIONS: You should store this material in a refrigerator. (NTP, 1992)

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

LD50 rat (young) oral 4900 mg/kg bw|LD50 Rat oral 1900 mg/kg|LD50 rat oral 3200 mg/kg bw

Dulcin is not known to occur as a natural product(1).

The only known use of dulcin was as a non-nutritive sweetner(1); use as sweetner is now banned in most countries(2). Dulcin's production and former use as a sweetner(1,2) 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 43(SRC), determined from a structure estimation method(2), indicates that dulcin is expected to have very high mobility in soil(SRC). The estimated Koc value for dulcin, which is a phenylurea compound, are consistent with observed Koc values for phenylurea compounds and herbicides such as phenylurea, tolylurea, chlorophenylurea, fenuron, fluometuron, methoxyphenylurea, metoxuron and others(SRC) which have Koc values in the in range of 20 to 75(3). Volatilization of dulcin from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.58X10-11 atm-cu m/mole(SRC), using a fragment constant estimation method(2). Dulcin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 9.8X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Phenylurea herbicides (such as linuron, metoxuron, fluometuron, siduron, monolinuron, isoproturon and chlorotoluron) have reported soil dissipation half-lives on the order of 10 to 100 days(4) with an approximate median soil dissipation half-life of 30 to 60 days(SRC); the soil dissipation rate of dulcin may be similar(SRC).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 43(SRC), determined from a structure estimation method(2), indicates that dulcin 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 1.58X10-11 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). According to a classification scheme(4), an estimated BCF of 3(SRC), from its estimated log Kow and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low. Ureas with chemical structures similar to dulcin have observed aqueous hydrolysis half-lives on the order of one year or more at environmental pHs(2). Dulcin has a UV absorption max at 290 nm(5) which indicates it may be susceptible to direct photolysis by sunlight(SRC).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), dulcin, which has an estimated vapor pressure of 9.8X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase dulcin 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 9 hours(SRC), calculated from its rate constant of 4.4X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). Particulate-phase dulcin may be removed from the air by wet or dry deposition(SRC). Dulcin has a UV absorption max at 290 nm(3) which indicates it may be susceptible to direct photolysis by sunlight(SRC).

The rate constant for the vapor-phase reaction of dulcin with photochemically-produced hydroxyl radicals has been estimated as 4.4X10-11 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 9 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Ureas with chemical structures similar to dulcin have observed aqueous hydrolysis half-lives on the order of one year or more at environmental pHs(1). Dulcin has a UV absorption max at 290 nm(2) which indicates it may be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 3 was calculated in fish for dulcin(SRC), using an estimated log Kow of 1.28(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of dulcin can be estimated to be 43(SRC). According to a classification scheme(2), this estimated Koc value suggest that dulcin is expected to have very high mobility in soil. The estimated Koc value for dulcin, which is a phenylurea compound, are consistent with observed Koc values for phenylurea compounds and herbicides such as phenylurea, tolylurea, chlorophenylurea, fenuron, fluometuron, methoxyphenylurea, metoxuron and others(SRC) which have Koc values in the in range of 20 to 75(3).

The Henry's Law constant for dulcin is estimated as 1.58X10-11 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that dulcin is expected to be essentially nonvolatile from water surfaces(2). Dulcin's Henry's Law constant indicates that volatilization from moist soil surfaces is not expected to occur(SRC). Dulcin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 9.8X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(1).

Occupational exposure to dulcin may occur through dermal contact with this compound at workplaces where dulcin is produced or used(SRC). Monitoring data were not available to indicate how the general population might be exposed to dulcin(SRC); however, dulcin's former use as sweetner (used in combination with saccharin)(1) would have exposed the general population through ingestion of food and beverages containing the compound(SRC).

After its oral administration to rats, dulcin is absorbed rapidly and is distributed throughout the body, with highest concentrations in the liver, kidneys, brain and lungs; tissue levels diminished to one-tenth within 24 hours after dosing.

... /Dulcin (DL)/ is excreted as a urinary ureido-N-glucuronide after oral administration to rabbits. ... Seven /UDP-glucuronosyltransferase (UGT)/ isoforms (UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT2B13, UGT2B14, and UGT2B16) have been identified from rabbit liver, but these UGTs have not been investigated using DL as a substrate. In this work, the identities of UGT isoforms catalyzing the formation of DL glucuronide were investigated using rabbit liver microsomes (RabLM) and cloned/expressed as rabbit UGT isoforms. DL-N-glucuronide (DNG) production was determined quantitatively in RabLM and homogenates of COS-7 cells expressing each UGT isoform by using electrospray liquid chromatography-tandem mass spectrometry. Analysis of DNG formation using RabLM, by Eadie-Hofstee plot, gave a Vmax of 0.911 nM/min/mg protein and the Km of 1.66 mM. DNG formation was catalyzed only by cloned expressed rabbit UGT1A7 and UGT2B16 (Vmax of 3.98 and 1.16 pmol/min/mg protein and a Km of 1.23 and 1.69 mM, respectively). Substrate inhibition of UGT1A7 by octylgallate confirmed the significant contribution of UGT1A7 to the formation of DNG. Octylgallate was further shown to competitively inhibit DNG production by RabLM (Ki = 0.149 mM). These results demonstrate that UGT1A7 is the major isoform catalyzing the N-glucuronidation of DL in RabLM.|... Dulcin (DL) possesses an ureido group that is metabolized by direct glucuronidation in rabbit liver microsomes. ...The glucuronidation of DL was studied using human liver microsomes (HLM) and expressed human UDP-glucuronosyltransferase (UGT) enzymes. The average K (m) and V (max) values from nine HLM samples were 2.10 mM and 0.156 nmol/mg/min, respectively. Of the six human UGT isoforms screened for their ability to glucuronidate DL, only UGT1A1 and UGT1A9 showed activity. The apparent K (m) values using UGT1A1 and UGT1A9 were 5.06 and 6.99 mM, and the apparent V (max) values were 0.0461 and 0.106 nmol/min/mg, respectively. Phenolphthalein, a substrate for UGT1A9, inhibited DL glucuronidation in HLM competitively (K (i) = 0.356 mM), but bilirubin, a substrate for UGT1A1, did not. These results suggest that UGT1A9 is a key enzyme catalyzing the glucuronidation of DL.|/It was/ found that 3% of a dose of dulcin was excreted unchanged in the urine of treated rabbits, 27% was excreted as dulcin N-glucuronide, a further 40% was excreted collectively as para-hydroxyphenylurea and its O-sulphate and O-glucuronide, and there were small amounts of urinary para-aminophenol.|Dulcin has known human metabolites that include (2S,3S,4S,5R)-6-[(4-ethoxyphenyl)carbamoylamino]-3,4,5-trihydroxyoxane-2-carboxylic acid.

Behaviors and taste-nerve responses to bitter stimuli are linked to compounds that bind T2 receptors expressed in one subset of taste-bud receptor cells (TRCs); and behavioral and neural responses to sweet stimuli are linked to chemical compounds that bind a T1 receptor expressed in a different TRC subset. Neural and behavioral responses to bitter-sweet mixtures, however, complicate the ostensible bitter and sweet labeled lines. In the golden hamster, Mesocricetus auratus, quinine hydrochloride, the bitter prototype, suppresses chorda tympani (CT) nerve responses to the sweet prototype: sucrose. This bitter-sweet inhibition was tested with concentration series of sucrose and dulcin, a hydrophobic synthetic sweetener that hamsters behaviorally cross-generalize with sucrose. Dulcin, sucrose and other sweeteners activate one subset of CT fibers: S neurons; whereas, quinine activates a separate subset of CT fibers: E neurons. Whole-nerve and S-neuron CT responses to a sweetener concentration series, mixed with 0, 1, 3 and 10 mM quinine, were measured for 0-2.5 s transient and/or 2.6-10 s steady-state response periods. Ten-sec total single-fiber records, aligned at response onset, were averaged for 100 ms bins to identify response oscillations. Quinine inhibition of dulcin and sucrose responses was identical. Each log molar increment in quinine resulted in equivalent declines in response to either sweetener. Furthermore, sucrose response decrements paralleled response increments in quinine-sensitive CT neurons to the same quinine increases. A 1.43 Hz bursting rhythm to the sweeteners was unchanged by quinine inhibition or decreases in sweetener concentration. Taste-bud processing, possibly between-cell inhibition and within-cell negative feedback, must modify signals initiated by T1 receptors before they are transmitted to the brain.|Variations in amplitude of responses of the chorda tympani to repeated application of various novel tastants were measured in familiarized and control groups of adult hamsters. Three groups of 10 hamsters were pre-exposed to 5 mM dulcin, 50 mM potassium L-glutamate (KGlu) or 1 mM 5'guanosine monophosphate (5'GMP). In the fourth group, the tongue was rinsed with 5'GMP for 20 min just prior to recording from the chorda tympani. The tastants were novel to the fifth group (naive control). A series of 17 stimuli was repeated six times and responses were quantified relative to the initial response of each of the 50 hamsters. The responses of the chorda tympani increased with repetition in the control group. In contrast, no increase in amplitude of response to the pre-exposed tastants or to stimuli with qualitatively related tastes was observed in the group familiarized with either KGlu or 5'GMP. These results indicate that the response of the chorda tympani depends on previous exposure to a tastant. The sensitivity of taste cells appears to be modulated, possibly by stimulus-induced supplementary receptors.|... /Investigators/ studied the role of alpha-gustducin in sweet taste. The behavioral and electrophysiological responses of alpha-gustducin knockout (KO) and wild-type (WT) mice to 11 different sweeteners, representing carbohydrates, artificial sweeteners, and sweet amino acids /was compared/. In behavioral experiments, over 48-h preference ratios were measured in two-bottle preference tests. In electrophysiological experiments, integrated responses of chorda tympani (CT) and glossopharyngeal (NG) nerves were recorded. /It was/ found that preference ratios of the KO mice were significantly lower than those of WT for acesulfame-K, dulcin, fructose, NC00174, D-phenylalanine, L-proline, D-tryptophan, saccharin, SC45647, sucrose, but not neotame. The nerve responses to all sweeteners, except neotame, were smaller in the KO mice than in the WT mice. The differences between the responses in WT and KO mice were more pronounced in the CT than in the NG. These data indicate that alpha-gustducin participates in the transduction of the sweet taste in general.

SYMPTOMS: Ingestion of 20-40 g in adults produced dizziness, nausea, methemoglobinemia with cyanosis and hypotension. ACUTE/CHRONIC HAZARDS: When heated produces hazardous decomposition products. (NTP, 1992)

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

/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/

/HUMAN EXPOSURE STUDIES/ Thorough studies on human volunteers, including several diabetics, showed that the ingestion of 0.1-0.6 g dulcin/day for one year produced no adverse effects.|/SIGNS AND SYMPTOMS/ In adults, doses of 20-40 g dulcin produces dizziness, nausea, methemoglobin with cyanosis, hypotension and, in one case, coronary disturbance.|/CASE REPORTS/ Two deaths in children have been associated with the ingestion of 8-10 g dulcin.|/OTHER TOXICITY INFORMATION/ ...The glucuronidation of /dulcin (DL)/ was studied using human liver microsomes (HLM) and expressed human UDP-glucuronosyltransferase (UGT) enzymes. ... Phenolphthalein, a substrate for UGT1A9, inhibited DL glucuronidation in HLM competitively (K (i) = 0.356 mM), but bilirubin, a substrate for UGT1A1, did not. ...|/OTHER TOXICITY INFORMATION/ Psychophysical cross-adaptation experiments were performed with two carbohydrates, sucrose (SUC) and fructose (FRU), and two sweeteners, acesulfame-K (MOD) and dulcin (DUL). Seven subjects were asked to match concentrations that elicited the same intensity as a sucrose reference (30 g/L). Cross-adaptation levels were calculated as the ratio of isointense concentrations measured for a given stimulus before and under adaptation. ... Significant and reciprocal cross-enhancement is observed between DUL and MOD (approximately -20%, P < 0.03), and also between SUC and DUL (approximately -15%, P < 0.08). In parallel, molecular modeling of the four tastants was performed in order to look for the 12 common binding motifs that were isolated on 14 other tastants in a previous study. ...DUL and MOD only display four and five distinct motifs respectively and do not have any motif in common. Experimental cross-adaptation levels seem to correlate well with the number of motifs that molecules have in common. ...DUL and MOD do not share any motif and do not cross-adapt. ...

dulcin

Dulcin achieved some practical importance as a sweetener, despite safety concerns. It was blended with saccharin or sodium saccharin in order to mask the aftertaste of saccharin. As some dulcin metabolites were considered potentially hazardous, it is now banned in most countries.|Compared with dilute sucrose solutions, it is approximately 250 times sweeter. Sweetness characteristics are good.

Dulcin has been determined by thin-layer chromatography in carbonated drinks and fruit juices, with limits of detection of 5 and 7 mg/kg, respectively; in a variety of soft drinks, with a limit of detection of 0.03%: and in some Japanese foods, with a limit of detection of 1-8 ug/mL. A detailed method for its determination in food products, with a detection limit ranging from 0.01-2 ug depending on the chromogenic spray reagent employed, includes a preliminary column chromatography clean-up. A comparison has been made of the sensitivity of different spray reagents on different thin-layer chromatography substrates, with detection limits for dulcin ranging from 0.1-1.0 ug. Paper chromatography has been used for its detection in foods, with a limit of 12.5 ug and in wine.

Food Additives -> SWEETENER; -> JECFA Functional Classes

Food Additives -> SWEETENER;