(4-Ethoxyphenyl)harnstoff

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.

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.

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.

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)

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 following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical.[Available from, as of June 21, 2012: http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=150-69-6]

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).

/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. ...

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).

AEROBIC: In Warburg respirometer studies using activated sludge inoculum at 2500 mg/L from three sewage treatment plants in Tennessee and a 144-hour incubation period, dulcin (present at 500 mg/L) was found to be toxic (inhibitory or lethal to sludge organisms) using Ashland City sludge(1); using Nashville sludge, theoretical oxygen demand ranged from 1.9-13.0%(1); using Franklin City sludge, theoretical oxygen demand ranged from 5.8-24.2%(1).

Dulcin

Group 3: Not classifiable as to its carcinogenicity to humans

Volume 12: (1976) Some Carbamates, Thiocarbamates and Carbazides

1987

1987

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).

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).

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ A group of 20 male and 30 female rats was given oral incubations of 0.2 g/kg bw/day dulcin in Tween-methyl cellulose solution for 400 days (total dose, 17 g), at which time 60% of the animals were still alive. Half of these animals received no dulcin from then on and were observed until death; the remaining animals continued to receive the dulcin treatment, and total doses of up to 33 g/animal were given. No malignant tumors were reported. Of 30 controls given the Tween-methyl cellulose vehicle alone, one developed a fibroadenoma. During the experiment an unstated number of treated males and 20 treated females were mated; the 39 male offspring were treated at 8 weeks of age with 0.2 g/kg bw/day for 660 days (total dose, 29 g), at which time the 5 survivors were killed. No malignant tumors were reported.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ A group of 80 white rats (sex unspecified) received different doses of dulcin for lifespan. Fifteen rats receiving 0.2 g/kg bw/day survived 12 months, and the last rat survived 22 months; no carcinogenic effect was seen.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ A group of 30 14-week old rats (mainly male, strain not specified) was fed 20 g of a diet containing 1% commercial dulcin (m.p. 169-170 °C) daily for up to 24 months. Thirty rats fed the basal diet alone served as controls. All of 30 rats which received a diet containing 0.1% butter yellow and served as positive controls died with liver tumors within 21-24 months. After one year, 26 dulcin-treated rats and 26 controls were alive; by the end of the experiment, 9 treated and 13 control rats were still alive. Papillomas of the pelvic epithelium and of the bladder occurred in about 75% of 23 treated animals and in none of 19 controls. Stones were present in the renal pelvis and bladder of about 66% of the 23 treated animals. All stones were associated with papillomas, but the papillomas did not always occur in the area of the urinary tract where the stone was located.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Groups of 10-25 male rats (strain not specified) were fed diets containing 0, 0.001, 0.01, 0.1, 0.5 or 1% dulcin for 2 years. After 18 months, 7/10, 7/10, 7/10, 8/20, 7/20 and 4/25 rats in the respective groups were still alive; no liver tumors were observed.

For more Non-Human Toxicity Excerpts (Complete) data for Dulcin (6 total), please visit the HSDB record page.

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).

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).

Artificial sweetening agent, prohibited by FDA for use in foods.

Non-nutritive sweetener

From p-aminophenol

... Produced from the addition of potassium cyanate to p-phenetidine hydrochloride in aqueous solution at room temperature or from mixing urea and p-phenetidine hydrochloride to a mixture of hydrochloric acid and glacial acetic acid.

Made by treating p-phenetidine with phosgene and then with ammonia.

Food Additives -> SWEETENER -> JECFA Functional Classes

Food Additives -> SWEETENER -> JECFA Functional Classes

Food Additives -> SWEETENER -> JECFA Functional Classes

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.