PAGE INTENTIONALLY LEFT BLANK William C. Herz Director of Scientific Programs M E M O R A N D U M TO: Product Testing Recipient FROM: William C. Herz, Director, Scientific Programs SUBJECT: Urea Product Testing Dossier DATE: March 15, 2003 It is with great pleasure that The Fertilizer Institute ( TFI) announces the completion and distribution of the final product testing dossier for Urea ( CAS # 57 13 6).

As you are aware, TFI sponsored this four   year program to develop and summarize screeninglevel hazard information for high production volume ( HPV) chemicals. The data elements generated represent a broad overview of human health and ecological parameters. These include a physical  chemical characterization, environmental fate, mammalian toxicity and ecotoxicity. A health and environmental safety data summary dossier was prepared for each of the 23 materials. It summarizes the available literature data, new testing data, category description and read across data as well as provides a conclusion regarding the inherent hazards of the material.

Upon receipt of this data a 90 calendar day regulatory trigger starts within which you must update your material safety data sheets ( MS DS). Upon first product shipment you must also notify your distributors and employers once the MS DS has been updated. These regulatory requirements are detailed in 29 CFR 1910.1200( g)( 5) and 29 CFR 1910.1200( g)( 6)( i). The requirements are found in the Occupational Safety and Health Administration " Hazard Communication Standard" ( 29 CFR 1910.1200).

Please note that by receipt of this data; you agree not to distribute or sell this data beyond your own company. PAGE INTENTIONALLY LEFT BLANK HEALTH & ENVIRONMENTAL SAFETY DATA SUMMARY DOCUMENT UREA CAS # 57 13 6 Prepared for THE FERTILIZER INSTITUTE January 27, 2003 THE WEINBERG GROUP INC. 1220 Nineteenth St, NW, Suite 300 Washington, DC 20036 2400 e mail science@ weinberggroup. com WASHINGTON NEW YORK SAN FRANCISCO BRUSSELS PARIS PAGE INTENTIONALLY LEFT BLANK TABLE OF CONTENTS Page EXECUTIVE OVERVIEW............................................................................................................... 1 SIDS DATA PROFILE...................................................................................................................... 3 SIDS SUMMARY.............................................................................................................................. 4 1. GENERAL INFORMATION ............................................................................................... 7 2. PHYSICAL CHEMICAL DATA ......................................................................................... 16 3. ENVIRONMENTAL FATE AND PATHWAYS................................................................. 23 4. ECOTOXICITY.................................................................................................................... 27 5. TOXICITY............................................................................................................................ 36 6. REFERENCES...................................................................................................................... 59 1 Urea ( CAS # 57 13 6) EXECUTIVE OVERVIEW The Fertilizer Institute, on behalf of its member companies, initiated a Product Testing Project to collect, review, summarize, and where necessary develop additional health and environmental safety data for 23 of its high production volume inorganic fertilizer materials. These data and summaries provide valuable information that can be used to update Material Safety Data Sheets, answer customers' questions, and support product stewardship efforts. The chemical industry is also participating in a voluntary program of comparable scope for high production volume organic chemicals. 1 The 23 fertilizer materials were divided into five categories ( i. e., ammonia compounds, nitrate compounds, phosphate compounds, salts and acids) based on their primary constituents as shown in Table 1. The use of categories is a recognized and accepted method that allows health and environmental safety data from one chemical in the category to be used to represent one or more other related chemicals in the category. The key is to find similar, or at least predictable, patterns and trends among the chemicals in a category. In this way, data can be pooled, resources are optimized, and fewer animals are used in testing, all without losing the ability to evaluate the hazards and safety of the individual chemicals. Note that some of the materials fall into more than one category ( e. g., urea is in both the nitrate and ammonia categories).

Searches were conducted using on line databases, standard scientific data compendia, and other published sources for toxicity, ecotoxicity, environmental fate, and physical chemical properties. The collected data were reviewed for quality and acceptability and then summarized according to the Organization for Economic Cooperation and Development ( OECD) Screening Information Data Set ( SIDS) dossier format. The OECD countries ( including the United States) have agreed on a set of tests and on types of data that are generally necessary to characterize the chemical behavior and potential hazards of chemicals released into the environment. The OECD SIDS dossier was chosen as a standard format for the TFI Product Testing Project in order that it would be scientifically defensive, broadly applicable and easily understandable to a wide range of stakeholders.

Urea is unique among the 23 fertilizer materials in that an OECD SIDS dossier is already available2. Finland sponsored development of the dossier which was published by OECD in 1994. A brief exposure and risk evaluation was prepared in addition to the health and environmental data summary. It concluded that there was no indication for concern for human health and the environment and that no further testing was needed for urea.

The following pages provide the health and environmental data from the urea dossier in the same format as the other 22 fertilizer materials and, in some cases, translated from the original data sheets in German. No additional searching for data was conducted.

1 HPV Chemical Challenge Program; USEPA 1999 ( http:// www. epa. gov/ opptintr/ chemrtk/ volchall. htm) 2 OECD SIDS Dossier   Urea ( CAS # 57 13 6)  4.5.1994. 60 pages 2 Urea ( CAS # 57 13 6) TABLE 1: CATEGORIES FOR PRODUCT TESTING PROJECT CATEGORY COMPOUND CAS NUMBER Ammonia Compounds Anhydrous ammonia Aqua ammonia Ammonium nitrate Ammonium sulfate Ammonium thiosulfate Nitrogen solutions ( UAN) Ammonium phosphate sulfate Diammonium phosphate ( DAP) Monoammonium phosphate ( MAP) Urea 7664 41 7 1336 21 6 6484 52 2 7783 20 2 7783 18 8 15978 77 5 12593 60 1 7783 28 0 7722 76 1 57 13 6 Nitrate Compounds Sodium nitrate Ammonium nitrate Potassium nitrate Potassium sodium nitrate Nitrogen solutions ( UAN) 7631 99 4 6484 52 2 7757 79 1 7757 79 1/ 7631 99 4 15978 77 5 Phosphate Compounds Diammonium phosphate ( DAP) Monoammonium phosphate ( MAP) Liquid polyphosphate Single superphosphate** Granular triple superphosphate** 7783 28 0 7722 76 1  8011 76 5 65996 95 4 Salts Potassium chloride Potassium magnesium sulfate Potassium nitrate Potassium sodium nitrate Potassium sulfate Calcium sulfate 7447 40 7 14168 73 1 7757 79 1 7757 79 1/ 7631 99 4 7778 80 5 7778 18 9 Acids Phosphoric acid Nitric acid Sulfuric acid 7664 38 2 7697 37 2 7664 93 9 * = Nitrogen solutions are represented largely by Urea Ammonia Nitrogen ( UAN; 15978 77 5) ** = Single superphosphate and granular triple superphosphate are combined into a single dossier.  = No CAS number readily available 3 Urea ( CAS # 57 13 6) SIDS DATA PROFILE Date: April 5, 1994 1.01 A. CAS No. 57 13 6 1.01 C. CHEMICAL NAME ( OECD NAME) Urea 1.01 D CAS DESCRIPTOR Urea 1.01 G STRUCTURAL FORMULA CH4N2O OTHER CHEMICAL IDENTITY INFORMATION N/ A 1.5 QUANTITY World production   41 60 million tons during 1985 1989 1.7 USE PATTERN In US   fertilizer ( solid and solutions) 73% export 13% urea   formaldehyde resins and adhesives 5% other e. g., animal feeds, melamine, consumer products 9% 1.9 SOURCES AND LEVELS OF EXPOSURE Some manufacturing and use ( e. g., fertilizer application) occupational exposure possible. Some release to the environment is likely during use. Maximum concentration in consumer products is generally 1%. Urea is the end by product of biochemical protein decomposition and the main solid component of urine. ISSUES FOR DISCUSSION ( IDENTIFY, IF ANY) No additional testing needed. 4 Urea ( CAS # 57 13 6) SIDS SUMMARY Date: April 5, 1994 CAS No: 57 13 6 SPECIES PROTOCOL RESULTS PHYSICAL CHEMICAL DATA Melting Point 133oC Boiling Point 135oC ( at 101 kPa) ( decomposes) Density 750 kg/ m3 Vapour Pressure Calculated 80 Pa at 20oC Partition Coefficient ( log Kow)  1.59 at 20 25oC Water Solubility 1,193 g/ l at 25oC pH 7.2 ( 100 g/ l) Oxidation: Reduction potential  ENVIRONMENTAL FATE and PATHWAY Photodegradation  Stability in Water Calculated T1/ 2 > 1 year Monitoring Data  Transport and Distribution Calculated ( Fugacity Level 1 type) In Air 0.16% In Water 99.84%

Biodegradation OECD TG 302 B SCAS 24 hr. Ultimately biodegradable 93 98% ECOTOXICITY Acute toxicity to Fish Barillius barna LC50 ( 96 hr) > 9,100 mg/ l Acute toxicity to Daphnia Daphnia magna DIN 38412 Tell 11 ( modified) EC50 ( 24 hr) > 10,000 mg/ l Toxicity to Algae Scenedesmus quadricauda Cell multiplication inhibition test TT ( 192 hr) > 10,000 mg/ l Toxicity to Soil Dwelling Organisms Applications of nitrogenous fertilizers to grassland for long period may have deleterious effects on earthworms in the absence of liming. Toxicity to Terrestrial Plants Glycine max ( L.) Merr. Max. concentration at which no effect was observed during the test period: < 0.01 w % urea of dry weight of leafs (= 9 mg/ leaf, a 7 day study) Toxicity to Birds Pigeon LDLO = 16,000 mg/ kg subcutaneous TOXICITY Acute Oral Rat Mouse Cattle LD50 = 14,300 15,000 mg/ kg LD50   11,500 13,000 mg/ kg LD50 = 510 mg/ kg 5 Urea ( CAS # 57 13 6) CAS No: 57 13 6 SPECIES PROTOCOL RESULTS Acute Inhalation  Acute Dermal  Mouse 12 mo carcinogenicity screening NOAEL = 6750 mg/ kg Repeated Dose Rat 12 mo carcinogenicity screening NOAEL = 2250 mg/ kg Genetic Toxicity in vitro . Gene mutation Salmonella Ames test  ( with metabolic activation)  ( without metabolic activation)

Chinese hamster fibroblast Chromosomal aberration test + at 216 mM ( without metabolic activation)( very high dose) Mouse lymphoma L5178Y/ Tk +/ Mouse lymphoma TK locus assay + at 530 662 mM +/ at 265 379 mM  at 132 mM ( without metabolic activation) . Chromosomal aberrations Mouse lymphoma L5178Y/ Tk +/ Analysis of DNA singlestrand breaks + at 628 718 mM  at 359 539 mM ( without metabolic activation) Genetic Toxicity in vivo Mouse Bone marrow cytogenetic test + 7 fold rate of aberrations compared to controls; mice were fed with urea 500 mg per animal per day for 5 days ( extremely high dose) Mouse Long term Not carcinogenic Carcinogenicity Rat dietary studies Not carcinogenic Mouse 12 month carcinogenicty screening No toxic effects in gonads reported at dose levels up to 6750 mg/ kg/ d Reproduction Toxicity Rat 12 month carcinogenicity screening No toxic effects in gonads reported at dose levels up to 2250 mg/ kg/ d Development/ Teratogenicity Rat Urea ( 50 g/ kg/ d) was given in 2 doses 12 h apart by gavage for an average of 14 days No outstanding ( external) teratogenicity was noted, the mean birthweight was lower but the litter size was greater Skin Irritation Human Experience May be irritating at > 10% concentration; not a skin sensitizer 6 Urea ( CAS # 57 13 6) CAS No: 57 13 6 SPECIES PROTOCOL RESULTS Human Experience Despite extensive, long term use in dermatology, no contact allergy or marked side effects have been reported. Human SLADH patients receiving urea orally ( 30 g/ d) up to 5 years did not exhibit side effects 7 Urea ( CAS # 57 13 6) 1. GENERAL INFORMATION 1.01 SUBSTANCE INFORMATION * A. CAS number 57 13 6 B. Name ( IUPAC name) Urea * C. Name ( OECD name) Urea * D. CAS Descriptor ( where applicable for complex chemicals)

E. EINECS Number 200 315 5 F. Molecular Formula CH4N2O * G. Structural Formula H2N\ C= O H2N/

H. Substance Group < text begins here> ( If possible, only for petroleum products, see HEDSET explanatory note)

I. Substance Remark < text begins here> ( Indicate the substance remark as prescribed in the EINECS Inventory, if possible)

J. Molecular Weight 60.06 1.02 OECD INFORMATION A. Sponsor Country Finland B. Lead Organization Name of Lead Organization: National Board of Waters and the Environment Contact Person: Mr. Jukka Malm Address/ Phones: P. O. B. 250 SF 00101 Helsinki FINLAND Tel: + 358 0 69 51 388 Fax: + 358 0 69 51 381 8 Urea ( CAS # 57 13 6) C. Name of Responder ( Information on a responder should be provided when companies respond to Lead Organization or SIDS Contact Points.)

Name: Mr. Jukka Malm Address/ Phones: P. O. B. 250 SF 00101 Helsinki FINLAND Tel: + 358 0 69 51 388 Fax: + 358 0 69 51 381 1.1 GENERAL SUBSTANCE INFORMATION A. Type of Substance element [ ]; inorganic [ X]; natural substance [ X]; organic [ ]; organometallic [ ]; petroleum product [ ] Urea is considered an organic compound by some regulatory agencies.

B. Physical State ( at 20 ° C and 1.013 hPa)

gaseous [ ]; liquid [ ]; solid [ X]

C. Purity 98 99 wt % ( Indicate the percentage by weight/ weight)

1.2 SYNONYMS Carbamide Carbonyl diamide 1.3 IMPURITIES [ Indicate CAS No., chemical name ( IUPAC is preferable), percentage, if possible EINECS number.]

CAS No.: EINECS No.: Name: Biuret Value: 0.3   2 wt % Remarks: Kirk Othmer Encyclopedia Name: Methylenediurea Value: 1.3 2.2% Remarks: Testing results indicate that inclusion of these materials does not adversely affect toxicity. 9 Urea ( CAS # 57 13 6) 1.4 ADDITIVES [ e. g. stabilizing agents, inhibitors etc. Indicate CAS No., chemical name ( IUPAC name is preferable), percentage, if possible EINECS number, the component of the UVCB substance with no defined composition) should be indicated here.]

CAS No.: EINECS No.: Name: Urea formaldehyde binder can be used in some prilling processes Value: < text> Remarks: < text>

* 1.5 QUANTITY [ Information on production or import levels should be provided in figures or ranges ( e. g. 1,000 5,000; 5,000 10,000 tonnes, etc.; see SIDS Manual) per responder or country and the date for which those ranges apply should be given. For EU Member states, only indicate the EU import figure. Give an estimation of the global production quantity in the remarks field. Information on the number of producers in the country and the source of information should also be given in the remarks field.)

Remarks: Production figures ( 1985 1989) in metric tons N USA 1,470,000   2,350,000 Total NA 3,140,000   6,278,000 Total SA 644,000   949,000 Total Asia 8,063,500   12,185,000 Total Europe 7,144,900   8,321,000 World Total 19,062,400   27,963,000 ( as urea) 41,440,000   60,789,000 ( urea N   46%) References: FAO Yearbook, Fertilizer, 1990 1.6 LABELING AND CLASSIFICATION ( If possible, enter information on labeling and classification, such as labeling and classification system, existence of specific limit, symbols, nota, R Phrases and S Phrases of EC Directive 67/ 548/ EEC. See HEDSET Explanatory Note.)

Labeling Type: < text> Specific limits: None Symbols: < text> Nota: < text> R phrases: None S phrases: None Text of S phrases: < text> Remarks: < text>

Classification Type: < text> 10 Urea ( CAS # 57 13 6) Category of danger: < text> R phrases: < text> Remarks: < text>

Recommended precautions and summary of safety data sheets Main hazardous properties: Pure, uncontaminated urea is a stable, safe product to handle. It does not pose a toxicity, fire or explosion problem and is not generally considered hazardous when exposed to open flame. It does not polymerize. However, instability can result with exposure to hypochlorites. An unstable explosive compound ( nitrogen trichloride) can result.

Incompatibilities with gallium perchlorate, permanganate, dichromate, nitrate and chlorine exist. Avoid contact with caustics and alkalies. Urea may form cyanuric acid, HOCNC( OH) NC( OH) N2H2O, in aqueous solutions at elevated temperatures. In the presence of strong alkalies at elevated temperatures, urea can form metal cyanates that, if swallowed, can be metabolized in the body to form toxic cyanides.

Fire: Urea has no fire or explosion hazards unless it is heated to the point of decomposition whereby flammable gas can be given off. The compound is not generally considered hazardous if exposed to open flame. Urea dust clouds have been reported to withstand a temperature of 900oC ( 1650 F) without igniting.

Human health: Urea is not considered toxic to humans or animals, although certain individuals experience skin sensitivity. It is a diuretic and a topical keratolytic and antiseptic. The major health hazard is the possibility of skin burns on contact with molten urea during processing or in case of fire.

Excessive inhalation of dust may cause irritation, coughing and labored breathing ( especially workers with asthma). Urea is irritant to the eyes and mucous membranes. Prolonged skin contact may cause mild irritation and redness. Ingestion can cause nausea, gastric irritation, diarrhea and stomach pain. Individuals with kidney impairment or asthmatic condition should have physician's approval before working with urea dust.

Environment: Large spills can contaminate soil, surface and ground water.

Storage: The problems associated with urea bulk storage are primarily related to incompatibility with other fertilizer products. Urea itself is hygroscopic when humidity is over 75 percent, picking up water readily from humid atmospheres. When urea becomes contaminated with other fertilizer materials, particularly with ammonium nitrate or phosphate fertilizers, its hygroscopicity is sharply increased, presently serious pile setting and caking problems.

Handling precautions: Use good housekeeping techniques that will facilitate keeping airborne particulates and dust deposits at a minimum. Avoid breathing urea dust. Avoid prolonged or repeated skin contact. Practice good personal hygiene daily to minimize industrial dermatitis 11 Urea ( CAS # 57 13 6) and/ or irritation. ( Remove work clothes and shower before going home daily). Keep urea away from food and beverage.

When hopper cars or bulk trucks loaded with liquid or solid urea are opened, ammonia vapor and carbon dioxide may accumulate above the product. Enter hoppers or vessels only after removing any vapor accumulations by proper ventilation.

Personal protection: Use protective gloves or skin barrier cream to avoid skin rash or irritation. High concentrations of dust call for the use of protective dust respiratory devices. When work is performed around urea processing areas, hot liquid or airborn dust particles may escape; therefore, use appropriate personal protective equipment. Workers should use a face shield or chemical goggles, rubber elbow length gloves and a rubber rain suit in such environments. Workers should wear rubber footwear since urea solutions are very corrosive to leather.

First aid: Skin burns: If molten urea is spilled on the skin, flush with water to remove the heat from the urea, which would otherwise continue to produce skin burns until cooled. Then wash gently with mild soap and water. Send victim to physician to have burned area examined.

Eye contact: Hold eyes open and flush thoroughly with running water for 15 20 minutes. If any irritation or redness persists, see a physician or ophthalmologist.

Skin contact: Wash affected area thoroughly with soap and water. Remove all contaminated clothing. If serious conditions persist, see physician or dermatologist.

Inhalation: Remove victim to fresh air to restore or support breathing. Administer oxygen is breathing is still labored. For persisting conditions, consult a physician.

Ingestion: Have victim drink 2 L of water or saline solution to dilute stomach contents. Seek medical help for further treatment, observation and support after first aid.

Extinguishing: Fire fighters should wear self contained breathing apparatus in fires where urea is being stored. Thermal and oxidative degradation products can include ammonia, cyanuric acid, biuret and carbon dioxide.

Spillage and disposal procedure: Spill and leak procedures for urea are as follows: Sweep up or scoop up spilled material for recovery or disposal. Using a dedusting agent ( sweeping compound, moist sand, etc.) and ventilating the area are recommended to keep dust levels low. Avoid contamination of spilled urea with oxidizing agents or nitrates. Flush residue with copious water. Treat airborne urea dust by using a fine water spray and local ventilation.

Small leaks and spills of urea to aqueous environments are generally handled by diluting the urea water mix and discharging into the waste stream.

Large leaks or spills to aqueous environments entail recycling and reprocessing the ureacontaminated water to regenerate the spilled urea. ( Once again, note and avoid incompatibilities.) 12 Urea ( CAS # 57 13 6) Dispose of urea wastes and spills by burial in an approved landfill or possibly spread on farmland as fertilizer ( provided other contaminants allow this use). Incineration is another option. Use a licensed waste hauler, documenting all procedures, destinations, etc. Make sure the urea waste is disposed of in accordance with federal, state or local regulations, following the strict regulations. Reference: National Safety Council, UREA: Safe Use and Handling, Data Sheet I   691 Rev. 90.

* 1.7 USE PATTERN A. General [ Data on use pattern have to be given by assigning main types according to their exposure relevance ( i. e. non dispersive use, use in closed systems, use resulting in inclusion into or onto matrix and wide dispersive use), industrial categories ( e. g. basic chemical industry, chemical industry, agricultural industry, personal and domestic use) and use categories such as coloring agents, intermediates, solvents, adhesives, cleaning/ washing agents, fertilizers, impregnation agents, surface active, etc. If available, give an estimation of different uses in percentage terms. See SIDS Manual for guidance.]

Type of Use: Category:

( a) main nitrogenous fertilizer industrial use ( b) main animal feed supplement at approximately 1% of ration industrial use Remarks: ( a) Manufacturing and use in industry: In modern synthetic processes, urea is made by reacting ammonia and carbon dioxide at high pressure and high temperature to form ammonium carbamate and simultaneously dehydrating the ammonium carbamate to urea and water. Produced urea is purified by crystallization.

Occupational and environmental exposure during production is possible due to accidental process breakdowns and disorders in reactor operations, pumping cycles, evaporation and crystallization processes, in maintenance, loading and unloading operations. Potential occupational exposure occurs via inhalation of aerosols from urea melt and hot saturated solutions, or splashes to skin or eyes, or inhalation of dust.

Consumption patterns in USA: 13 Urea ( CAS # 57 13 6) Fertilizer, solid 42% fertilizer solutions 31%; exports 13%; ureaformaldehyde resins and adhesive 5%; other, including animal feeds and melamine 9%.

( b) < text>

Reference: Vershueren, K. Handbook of Environmental Data on Organic Chemicals, 2nd Edition. Van Nostrand Reinhold, 1983. p. 1178. Altman, P. L. and Dittmar, D. S. 1974. Biology Data Book, Vol. III, 2nd Ed. Federation of American Societies for Experimental Biology. p. 1494.

B. Uses in Consumer Products [ If the chemical is present in consumer products as marketed, give details of products' function ( e. g. detergent, etc.), and percentage in product and physical state of product as marketed ( e. g. aerosol, powder or liquid)]

Function Amount present Physical State Cleaning products, Up to 1% Varies cosmetics, foods Remarks: Urea is used in liquid soaps, detergents and household cleaning products. It is also used in cosmetics products as creams, shampoos, hair conditioners, hair dyes and dye removers, in ammoniated dentifrices etc. Maximum urea concentration is commonly 1%. Urea peroxide ( 10 15%) preparations for tooth bleaching yield urea ( 6.4 9.6% of weight).

Urea is a natural constituent of many common foodstuffs. Oats may contain 4.5 percent of their total nitrogen content as urea and oil seed meals about 0.25 percent. Up to 15 percent of the total nitrogen of young plants and about 5 percent of the mature plants is nonproteinaceous and much is in the form of urea. Urea is a normal constituent of animal tissues and fluids and is ingested in small amounts when meat is consumed. References: Svensson, Kaj and Yhdistys, Suomen Teknokemian ( Cosmetics and Detergent Association in Finland), May 1992. FDA, PB 288673. 1978. Evaluation of the Health Aspects of Urea as a Food Ingredient. Fasanaro, T. S. 1992. Bleaching teeth: History, chemicals and methods used for common tooth discolorations. J Esthet Dent. 4: 71 78. 14 Urea ( CAS # 57 13 6) 1.8 OCCUPATIONAL EXPOSURE LIMIT VALUE ( Indicate the type of occupational exposure limit value including short term exposure limit value. If a value does not exist, give the hygiene standard of the producer company if available. See also 5.11.)

OSHA permissible exposure levels: 15 mg/ m3 total dust 5 mg/ m3 respirable dust Exposure limit value Type: OSHA PEL Value: 15 mg/ m3 total dust; 5 mg/ m3 respirable fraction Remark: No specific limit has been set for urea, however, the federal OSHA PEL for particulates not otherwise regulated applies to all fertilizer dusts. In addition, AIHA established of Workplace Environmental Exposure Limit ( WEEL) of 10 mg/ m3 as a nonregulatory guidance number. Regulated limits may vary in local jurisdictions.

Short term exposure limit value Value: Not hazardous; however, the general guidance ( EH40 UK Health and Safety Executive) is that personal exposure to dust should be controlled to < 10 mg/ m3 ( 8 hr TWA) for inhalable dust and < 5 mg/ m3 ( 8 hr TWA) for respirable dust. Length of exposure period: < text> Frequency: < text> Remarks: < text> Reference: EFMA Website. Booklet No. 5 of 8: Production of Urea. 7. Occupational Health and Safety. Vershueren, K. 1983. Handbook of Environmental Data on Organic Chemicals, 2nd ed. Van Nostrand Reinhold, New York. p. 1178.

* 1.9 SOURCES OF EXPOSURE Describe sources of potential human [ other than concentration of chemicals in the workplace and indoor environment ( see 5.11)], or environmental exposure, including emission data ( e. g. quantities per media with information such as time dimensions of release, indication of type of release ( e. g. point source or diffuse), type of estimating ( e. g. average or worst case, uncertainties in estimation), for all phases of the life cycle of the chemical if available, including manufacturing and user areas.

For environmental exposure, indicate the production process briefly, number the sites of manufacture and, the basis for concluding that the process is " closed" if applicable.

Also an indication of measured exposure levels ( expressed in an appropriate form, e. g. geometric mean and standard deviation) can be mentioned here. Any information that 15 Urea ( CAS # 57 13 6) will help focus the assessment of exposure ( either qualitative or quantitative in nature) can be mentioned, if available).

Source: Media of release: < text here> Probable human exposure: The National Occupational Hazard Survey conducted by NIOSH estimated that in the USA 855 894 workers may be exposed to urea; 7% from actual observed use, 31% from observed use of a treadename product known to contain this chemical, and 62% from observed use of product in some type of general use which leads NIOSH to suspect that chemical may be contained in the product. [ NIOSH National Hazard Exposure Survey ( 1972 1974); as cited in HSDB 1991]. Remarks: Exposure in farming: The use of highly concentrated fertilizers in agriculture practice and in gardens can lead to human, livestock and pet exposure. Sources of exposure may be accidental inclusions of highly concentrated fertilizers in rations, application of fertilizers to fields with livestock, or washing of recently applied fertilizers by rain into water supplies of livestock. In some instances granular or liquid fertilizers may be accidentally spilled on land or into ponds, and in other instances fertilizer containers may be used for watering livestock without thorough cleaning and removal of residual fertilizers.

Environmental exposure: Various species of wild animals are exposed to urea when urea fertilizers are spread directly on the field and in the forests. Aquatic organisms are exposed to urea when recently applied fertilizers are washed by rain into rivers, lakes and seas.

Emission to soil: About 80% of produced urea is used as a fertilizer. Urea production capacities are expected to increase rapidly after 1992.

Emission to air: Urea is essentially non volatile. References: Oehme, F. W. and Barrel, D. S. 1986. Veterinary Gastrointestinal Toxicology, Chapter 17 in Rozman, K. and Hänninen, O. ( eds.), Gastrointestinal Toxicology, Elsevier Science Publishers, Amsterdam. p. 489 490. Informations Chimie No. 315, Mars 1990. p. 179 201. Environmental Canada: Tech Info for Problem Spills: Urea. 1985. p. 21 as cited in HSDB 1991.

1.10 ADDITIONAL REMARKS 16 Urea ( CAS # 57 13 6) A. Options for disposal [ Mode of disposal ( e. g. incineration, release to sewage system, etc.) for each category and type of use, if appropriate; recycling possibility.]

Remarks: Small leaks and spills of urea to aqueous environments are generally handled by diluting the urea water mix and discharging into the waste stream. Large leaks or spills to aqueous environment entail recycling and reprocessing the urea contaminated water to regenerate the spilled urea. ( Note and avoid incompatibilities.)

Water Spill: Contain by damming, water diversion or natural barriers. Remove and treat contaminated liquids. Absorb small amounts of liquid spill with natural or synthetic sorbents, shovel into containers and cover.

Landfill: Waste may be buried in an approved landfill or spread on farmland as fertilizer ( if other contaminants will allow this use). Incineration is another option. Use a licensed waste hauler, documenting all procudures, destinations, etc. Make sure the urea waste is disposed of in accordance with federal, state or local regulations following the strictest regulations. References: National Safety Council, UREA: Safe Use and Handling. Data Sheet I 691 Rev. 90. Environment Canada. 1985. Tech Info for Problem Spills: Urea. p. 2; as cited in HSDB 1991. United Nations, Treatment and Disposal Methods for Waste Chemicals ( IRPTC File), Date Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985, p. 295; as cited in HSDB 1991.

B. Other remarks Remarks: < text here> References: < text here>

2. PHYSICAL CHEMICAL DATA * 2.1 MELTING POINT ( If more than one, identify the recommended value.)

Value: 132.7 ° C; 133oC Decomposition: Yes [ X] No [ ] Ambiguous [ ] Sublimation: Yes [ ] No [ X] Ambiguous [ ] Method: [ e. g. OECD, other ( with the year of publication or updated of the method used)] Not mentioned 17 Urea ( CAS # 57 13 6) GLP: Yes [ ] No [ ] ? [ X] Remarks: On further heating decomposes to biuret, NH3 and cyanuric acid. On standing or on heating decomposes to NH3 and CO2. References: The Merck Index, 11th ed., Rahway, NJ., USA, Merck & Co., Inc. 1989. # 9781. BASF AG, AIDA, Grunddatensatz aus urea. 1991. Unpublished. KEMIRA B. V., Technical Information Data Sheet. 1998. Unpublished. Osol, A., Hoover, J. E., et al. ( eds.) Remington's Pharmaceutical Sciences, 15th ed., Easton, Pennsylvania, Mack Publishing Co. 1975. p. 864; as cited in HSDB 1991.

* 2.2 BOILING POINT ( If more than one, identify the recommended value.)

Value: 135 ° C Pressure: at 101kPa Method: [ e. g. OECD, other ( with the year of publication or updated of the method used)] Not mentioned GLP: Yes [ ] No [ ] ? [ X] Remarks: Urea decomposes before boiling References: BASF AG, AIDA, Grunddatensatz aus urea. 1991. Unpublished Environment Canada. 1985. Tech info for problem spills: urea.

* 2.3 DENSITY ( Relative Density) ( Where applicable, indicate the relative density of the substance.)

Type: Bulk density [ X]; Density [ ]; Relative Density [ ] Value: 750 kg/ m3 Temperature: ° C Method: [ e. g. OECD, other ( with the year of publication or updated of the method used)] Not mentioned GLP: Yes [ ] No [ ] ? [ X] Remarks: Specific gravity 1323 kg/ m3 at 20 24oC Density of water solution 1057 kg/ m3 10% ( w/ w) References: Weast, R. C. ( ed.). 1979. Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press, Inc. p. c 536; as cited in HSDB 1991. The Merck Index, 11th ed. 1989. Rahway, N. J., USA, Merck & Co., Inc. # 9781. 18 Urea ( CAS # 57 13 6) * 2.4 VAPOUR PRESSURE ( If more than one, identify the recommended value)

( a) Value: 80 Pa Temperature: 20 ° C Method: [ e. g. OECD, other ( with the year of publication or updated of the method used)] Calculated [ X]; measured [ ] Calculated according to Lyman et al. 1990. Handbook of Chemical Property Estimation Methods. American Chemical Society, Washington. GLP: Yes [ ] No [ X] ? [ ] Remarks: < text> References: National Board of Waters and the Environments. 1993. Unpublished data.

( b) Value: 1.73 KPa, 5.33 KPa Temperature: 20 and 40 ° C Method: [ e. g. OECD, other ( with the year of publication or updated of the method used)] Calculated [ ]; measured [ ] Not known; saturated water solutions GLP: Yes [ ] No [ ] ? [ X] Remarks: The values are graphically evaluated from the vapour pressure density diagram of urea water solutions presented in the reference. References: Environment Canada. 1985. Tech. info. for problem spills: Urea. p. 4 as cited in HSDB 1991. Kemira, B. V. 1988. Technical Information Data Sheet. p. 9 ( Unpublished).

* 2.5 PARTITION COEFFICIENT logPow ( If more than one, identify the recommended value)

( a) Log Pow:  1.59 Temperature: 20 25 ° C Method: [ e. g. OECD, other ( with the year of publication or updated of the method used)] Calculated [ ]; measured [ X] OECD Test Guideline 107, Flask shaking method. GLP: Yes [ ] No [ ] ? [ X] Remarks: The value of log Pow is given as reference substance value in OECD Test Guideline Method 107. 19 Urea ( CAS # 57 13 6) References: OECD Test Guideline for Testing Materials. 1981. Method 107, Paris.

( b) Log Pow:  2.97/ 2.26  2.59 Temperature: ° C Method: [ e. g. OECD, other ( with the year of publication or updated of the method used)] Calculated [ X]; measured [ ] Increment method von Rekker with computer program of Compudrug Ltd. GLP: Yes [ ] No [ ] ? [ X] Remarks: e. g., is the compound surface active or dissociative? References: Vershueren, K. 1983. Handbook of Environmental Data on Organic Chemicals, 2nd ed. Van Nostrand Reinhoild, NY. p. 1178. BASF AG, AIDA, Grunddatensatz aus urea, 1991, p. 2. Unpublished.

* 2.6 WATER SOLUBILITY ( If more than one, identify the recommended value)

A. Solubility Value: 780,000; 1,080,000; 1,193,000; 7,330,000 mg/ L Temperature: 5 ° C; 20oC; 25oC; 100oC Description: Miscible [ ]; Of very high solubility [ ]; Of high solubility [ X]; Soluble [ ]; Slightly soluble [ ] Of low solubility [ ]; Of very low solubility [ ]; Not soluble [ ] Method: [ e. g. OECD, other ( with the year of publication or updated of the method used)] Not mentioned GLP: Yes [ ] No [ ] ? [ X] Remarks: < text> References: BASF AG AIDA. 1991. Grunddatensatz aus urea. p. 2 Unpublished. Vershueren, K. 1983. Handbook of Environmental Data on Organic Chemicals, 2nd ed., Van Nostrand Reinhold, NY. p. 1178. Weast, R. C. ( ed.). 1979. Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979, p. c 536; as cited in HSDB 1991.

B. pH Value, pKa Value pH Value: 7.2 and 9.5 Concentration: 100,000 mg/ L ( water) 200,000 mg/ L ( water) 20 Urea ( CAS # 57 13 6) Temperature: ° C Method: [ e. g. OECD, other ( with the year of publication or updated of the method used)] Not mentioned GLP: Yes [ ] No [ ] ? [ X] ( Where applicable, enter values for the dissociation constant( s) and the conditions under which they were measured.) pKa value < text> at 25 ° C Remarks: < text> References: The Merck Index, 11th ed., Rahway, NJ, USA. 1989. # 9781. KEMIRA B. V., Technical Information Data Sheet. 1988. Unpublished.

2.7 FLASH POINT ( liquids)

Value: ° C Type of test: Closed cup [ ]; Open cup [ ]; Other [ ] Method: ( with the year of publication or updated of the method used) < text> GLP: Yes [ ] No [ ] ? [ ] Remarks: < text> References: < text>

2.8 AUTO FLAMMABILITY ( solid/ gases)

Value: ° C Pressure: < text> hPa Method: ( with the year of publication or updated of the method used) < text> GLP: Yes [ ] No [ ] ? [ ] Remarks: Non flammable and non combustible References: Hawley, G. G. 1977. The Condensed Chemical Dictionary, 9th ed., New York, Van Nostrand Reinhold Co. p. 905.

2.9 FLAMMABILITY Results: Extremely flammable [ ]; Extremely flammable   liquified gas [ ]; Highly flammable [ ]; Flammable [ ]; Non flammable [ X]; Spontaneously flammable in air [ ]; Contact with water liberates highly flammable gases [ ]; Other [ ] 21 Urea ( CAS # 57 13 6) Method: ( with the year of publication or updated of the method used) < text> GLP: Yes [ ] No [ ] ? [ ] Remarks: < text> References: Hawley, G. G. The Condensed Chemical Dictionary, 9th ed. New York, Van Nostrand Reinhold Co. 1977. p. 905.

2.10 EXPLOSIVE PROPERTIES Results: Explosive under influence of a flame [ ]; More sensitive to friction than m dinitrobenzene [ ]; More sensitive to shock than m dinitrobenzene [ ]; Not explosive [ X]; Other [ ] Method: ( with the year of publication or updated of the method used) < text> GLP: Yes [ ] No [ ] ? [ ] Remarks: < text> References: National Safety Council, Urea: Safe Use and Handling, Data Sheet I 691. Rev. 90.

2.11 OXIDIZING PROPERTIES Results: Maximum burning rate equal or higher than reference mixture [ ]; Vigorous reaction in preliminary test [ ]; No oxidizing properties [ ]; Other [ ] Method: ( with the year of publication or updated of the method used) < text> GLP: Yes [ ] No [ ] ?[ ] Remarks: < text> References: < text>

* 2.12 OXIDATION: REDUCTION POTENTIAL ( Where applicable, indicate the redox potential and the conditions under which it was measured.)

Value: < text> mV Method: ( with the year of publication or updated of the method used) < text> GLP: Yes [ ] No [ ] ?[ ] Remarks: < text> References: < text> 22 Urea ( CAS # 57 13 6) 2.13 ADDITIONAL DATA A. Partition co efficient between soil/ sediment and water ( Kd)

Value: < text> Method: [ e. g. OECD, other ( with the year of publication or updated of the method used)] < text> GLP: Yes [ ] No [ ] ?[ ] Remarks: < text> References: < text> 23 Urea ( CAS # 57 13 6) B. Other data [ e. g. Henry's Law constant, fat solubility, surface tension ( of aqueous solution), adsorption/ desorption on soil, particle size distribution, etc.]

Results < text> Remarks: < text> References: < text>

3. ENVIRONMENTAL FATE AND PATHWAYS [ Reporting of studies should give the test method, test conditions, ( laboratory versus field studies), test results ( e. g. % degradation in specified time period) and reference. Information on breakdown products ( transient and stable) should be provided when available.]

3.1 STABILITY * 3.1.1 PHOTODEGRADATION Type: Air [ ]; Water [ ]; Soil [ ]; Other [ ] Light source: Sunlight [ ]; Xenon lamp [ ]; Other [ ] Light spectrum: < text> nm Relative intensity: < text> ( based on intensity of sunlight) Spectrum of substance: [ e. g. lambda ( max.) (> 295 nm) and epsilon ( max.) or epsilon ( 295nm)] < text> nm Concentration of substance: < text> Temperature: ° C Direct photolysis: Half life: < text> Degradation: < text> % ( weight/ weight) after < text> ( exposure time) Quantum yield: < text> Indirect photolysis: Type of sensitizer: < text> Concentration of sensitizer: < text> Rate constant ( radical): < text> cm3/ molecule* sec Degradation: < text> Method: calculated [ ]; measured [ ] [ e. g. OECD, other( with the year of publication or updating of the method used)] GLP: Yes [ ] No [ ] ?[ ] Test substance: > text>, purity: < text> Remarks: < text> References: < text> 24 Urea ( CAS # 57 13 6) * 3.1.2 STABILITY IN WATER Type: Abiotic ( hydrolysis) [ X]; biotic ( sediment) [ ] Half life: > 1 yr at pH < text> at < text> ° C < text> at pH < text> at < text> ° C after < text> ( exposure time) Method: PCHYDRO model estimation GLP: Yes [ ] No [ X] ? [ ] Test substance: < text>, purity: < text> Remarks: ( e. g. CAS number, name and percentage of degradation products) Extremely slow References: National Board of Water and the Environment, Finland. 1994. Unpublished.

3.1.3 STABILITY IN SOIL Type: Field trial [ ]; Laboratory [ ]; Other [ ] Radiolabel: Yes [ ] No [ ] ? [ ] Concentration: < text> Soil temperature: < text> ° C Soil humidity: < text> Soil classification: DIN 19863 [ ]; NF X31 107 [ ]; USDA [ ]; Other [ ] Year: < text> Contents of clay etc.: Clay < text> %, Silt < text> %, Sand < text> % Organic carbon: < text> Soil pH: < text> Cation exchange capacity: < text> Microbial biomass: < text> Dissipation time: DT 50: < text> DT 90: < text> Dissipation: < text> % after < text> ( time) Method: [ e. g. OECD, others ( with the year of publication or updating of the method used)] GLP: Yes [ ] No [ ] ? [ ] Test substance: < text>, purity: < text> Remarks: < text> References: < text>

* 3.2 MONITORING DATA ( ENVIRONMENTAL) Note that data on biological effects monitoring, including biomagnification, and biotransformation and kinetics in environmental species are to be reported in section 4.7 and 4.8 respectively. Nonetheless, concentration in various biota should be reported here. Data on concentration in the workplace or indoor environment should be reported under 5.11.

Type of measurement: Background [ ]; At contaminated site [ ]; Other [ ] 25 Urea ( CAS # 57 13 6) Media: < text> Results: < text> Remarks: < text> References: < text>

3.3 TRANSPORT AND DISTRIBUTION BETWEEN ENVIRONMENTAL COMPARTMENTS INCLUDING ESTIMATED ENVIRONMENTAL CONCENTRATIONS AND DISTRIBUTION PATHWAYS ( e. g. during the chemical life cycle. The information should indicate whether the calculation is on a global basis or is site specific, and whether it is based on laboratory measurements or field observations.)

* 3.3.1 TRANSPORT Type of measurement: Adsorption [ ]; Desorption [ ]; Volatility [ ]; Other [ ] Media: < text> Method: < text> Results: < text> Remarks: < text> References: < text>

* 3.3.2 THEORETICAL DISTRIBUTION ( FUGACITY CALCULATION)

Media: air biota [ ]; Air biota sediment soil water [ ]; Soilbiota [ ]; Water air [ ]; Water biota [ ]; Water soil [ ]; Other [ ] Method: Fugacity level I [ ]; Fugacity level II [ ]; Fugacity level III [ ]; Fugacity level IV [ ]; Other ( calculation) [ ]; Other ( measurement) [ ] Results: < text> Remarks: < text> References: < text>

3.4 IDENTIFICATION OF MAIN MODE OF DEGRADABILITY IN ACTUAL USE Results: < text> Remarks: < text> References: < text>

* 3.5 BIODEGRADATION Type: Aerobic [ X]; Anaerobic [ ] Inoculum: Adapted [ X]; Non adapted [ ]; from sewage treatment activated sludge 26 Urea ( CAS # 57 13 6) Concentration of the chemical: 400 mg/ L related to COD [ ]; DOC [ ]; Text substance [ X] Medium: Water [ ]; Water sediment [ ]; Soil [ ]; Sewage treatment [ X] Degradation: ( percentage reduction/ exposure time) 3,52,60,85 and 96% decomposed after 3 hr., 7,10,14,16 days, respectively Results: ( see OECD guideline) Readily biodeg. [ ]; Inherently biodeg. [ X]; Under test condition no biodegradation observed [ ]; Other [ ] Kinetics: ( e. g. Zahn Wellens Test) < text> % in < text> ( time) Method: Inherent Biodegradability: OECD Guideline 302 B ( 1981) GLP: Yes [ ] No [ X] ? [ ] Test substance: Urea, purity: < text> Remarks: [ in case of poorly soluble chemicals, treatment given ( nature, concentration, CAS number, name and percentage of degradation products etc.)] Main mode of degradations is enzymatic mineralization References: BASF AG, Labor Oekologie, internal study ( Proj. 1/ 91/ 0452 ( 10/ 1).

3.6 BOD5, COD OR RATIO BOD5/ COD BOD5 Method: [ e. g. OECD, other( with the year of publication or updating of the method used)] Concentration: < text> related to COD [ ]; DOC [ ]; Test substance [ ] Value: < text> mg O2/ L GLP: Yes [ ] No [ ] ? [ ]

COD Method: < text> Value: < text> mg O2/ L GLP: Yes [ ] No [ ] ? [ ]

Ratio BOD5/ COD: < text> Remarks: < text> References: < text>

3.7 BIOACCUMULATION Species: < text> Exposure period: < text> Temperature: ° C Concentration: < text> 27 Urea ( CAS # 57 13 6) BCF: < text> Elimination: Yes [ ] No [ ] ? [ ] Method: [ e. g. OECD, other ( with the year of publication or updated of the method used)] < text> Type of test: Calculated [ ]; Measured [ ] Static [ ]; Semi static [ ]; Flow through [ ]; Other ( e. g. field test) [ ] GLP: Yes [ ] No [ ] ? [ ] Test substance: < text>, purity: < text> Remarks: Due to the low log Pow value, urea is not at all likely to undergo bioaccumulation. Urea is readily excreted from the body. References: < text>

3.8 ADDITIONAL REMARKS A. Sewage treatment ( Information on treatability of the substance)

Type: Semi continuous activated sludge ( SCAS) Degradation: 93 98% mean disappearance of urea in 24 hour cycle ( as determined by colorimetric analysis) Results: < text> Remarks: < text> References: EPA, Doc 878211481. 1983. Biodegradation testing of Santomelt 9909 CR and Ucar Runway de icer fluids, Monsanto Co., Analytical Chemistry Special Study 71 8. Job No. 14499006.

B. Other information [ Information that will help to focus the exposure assessment ( either qualitative or quantitative)]

Results: < text> Remarks: < text> References: < text>

4. ECOTOXICITY * 4.1 ACUTE/ PROLONGED TOXICITY TO FISH ( a) Type of test: Static [ X]; Semi static [ ]; Flow through [ ]; Other ( e. g. field test) [ ] Open system [ ]; Closed system [ ] Species: Barilius barna 28 Urea ( CAS # 57 13 6) Exposure period: 96 hr. Results: LC50 ( 96 hr): > 9,100 mg/ l NOEC = < text> mg/ L LOEC = < text> mg/ L Analytical monitoring: Yes [ ]; No [ ]; ? [ ] Method: [ e. g. OECD, other ( with the year of publication or updated of the method used)] < text> GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea Remarks: < text> References: Dodriyal A. K. and Bahuguna A. K. 1988. Himalayan Chem. Bull. 5, pp. 15 16.

( b) Type of test: Static [ X]; Semi static [ ]; Flow through [ ]; Other ( e. g. field test) [ ] Open system [ ]; Closed system [ ] Species: Leuciscus idus melanotus Exposure period: 48 hr Results: LC50 ( 48h) > 10,000 mg/ l NOEC = < text> mg/ L LOEC = < text> mg/ L Analytical monitoring: Yes [ ]; No [ ]; ? [ ] Method: [ e. g. OECD, other ( with the year of publication or updated of the method used)] < text> GLP: Yes [ ] No [ X] ? [ ] Test substance: Urea Remarks: < text> References: Juhnke, I., Lüdemann, D. 1978. Ergebnisse der Untersushung 200 chemischen Verbindungen auf akute Fischtoxicität mit dem Goldorfentest. Zeitschrift Wasser Abwasserforschung 11,5.

( c) Type of test: Static [ ]; Semi static [ ]; Flow through [ ]; Other ( e. g. field test) [ ] Open system [ ]; Closed system [ ] Species: Tilapia mossambica Exposure period: 96 hr Results: LC50 ( 96hr) = 22,500 mg/ L NOEC = < text> mg/ L LOEC = < text> mg/ L Analytical monitoring: Yes [ ]; No [ ]; ? [ ] Method: [ e. g. OECD, other ( with the year of publication or updated of the method used)] < text> GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea 29 Urea ( CAS # 57 13 6) Remarks: No mortality ( NOEC) at 20,000 mg/ L; 100% mortality at 25,000 mg/ L References: < text>

( d) Type of test: Static [ ]; Semi static [ X]; Flow through [ ]; Other ( e. g. field test) [ ] Open system [ ]; Closed system [ ] Species: Colisa fasciatus ( young tropical fresh water teleost) Exposure period: 96 hr. Results: LC50 ( 96h) = 5.0 mg/ L LC50 ( 48h) = 8.0 mg/ L LC50 ( 24h) = 9.0 mg/ L Analytical monitoring: Yes [ ]; No [ ]; ? [ ] Method: [ e. g. OECD, other ( with the year of publication or updated of the method used)] Not specified. GLP: Yes [ ] No [ X] ? [ ] Test substance: Urea Remarks: Study is partly inadequately reported. Results differ significantly from other acute toxicity results. Not a valid study. References: Pandey, K. and Shukla, J. P. 1983. Acta Hydrochim. et. Hydrobiol. 11,1. pp. 145 190.

4.2 ACUTE TOXICITY TO AQUATIC INVERTEBRATES * A. Daphnia Type of test: Static [ ]; Semi static [ ]; flow through [ ]; Other ( e. g. field test) [ ] Open system [ ]; Closed system [ ] Species: Daphnia magna Exposure period: 48 hrs. Results: EC50 ( 24h) > 10,000 mg/ l Analytical monitoring: Yes [ ]; No [ ]; ? [ ] Method: [ e. g. OECD, other ( with the year of publication or updated of the method used)] DIN 38412 Teil 11 ( modified) GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea Remarks: < text> References: Bringmann, G. und Kuhn, R. Zeitschrift für Wasser, und Abwasser. 1982. Forschung 15( 1) pp. 1 6. 30 Urea ( CAS # 57 13 6) * B. Other aquatic organisms ( a) Type of test: Static [ X]; Semi static [ ]; Flow through [ ]; Other ( e. g. field test) [ ] Open system [ ]; Closed system [ ] Species: Aedes aegypti larvae ( mosquito) Exposure period: 4 hr. Results: LC50 ( 4 hr) 60,000 mg/ l Analytical monitoring: Yes [ ]; No [ ]; ? [ ] Method: [ e. g. OECD, other ( with the year of publication or updated of the method used)] < text> GLP: Yes [ ] No [ X] ? [ ] Test substance: Urea Remarks: < text> References: Kramer, V. C., Schnell, D. J., and Nickerson, K. W. 1983. Journal of Invertebrate Pathology 42: 285 287.

( b) Type of test: Static [ X]; Semi static [ ]; Flow through [ ]; Other ( e. g. field test) [ ] Open system [ ]; Closed system [ ] Species: Entosiphon sulcatum ( protozoa flagellate) Exposure period: 72 hr Results: Toxicity Threshold ( TT) ( 72 hr): 29 mg/ l Analytical monitoring: Yes [ ]; No [ ]; ? [ ] Method: [ e. g. OECD, other ( with the year of publication or updated of the method used)] Cell multiplication inhibition test GLP: Yes [ ] No [ X] ? [ ] Test substance: Urea Remarks: In some extent urea exhibited selective toxic action on Entosiphon sulcatum. For example toxicity threshold for chloroform was > 6560 mg/ l. References: Bringmann, G. and Kühn, R. 1980. Water Research 14, pp. 231 241.

( c) Type of test: Static [ X]; Semi static [ ]; Flow through [ ]; Other ( e. g. field test) [ ] Open system [ ]; Closed system [ ] Species: Helisoma trivolvis ( freshwater snail) Exposure period: 24 hr Results: LC50 ( 24 hr) 14,241 mg/ 1 Helisoma trivolvis egg LC50 ( 24 hr) 18,255 mg/ 1 Helisoma trivolvis juveniles LC50 ( 24 hr) 30,060 mg/ 1 Helisoma trivolvis adults Analytical monitoring: Yes [ ]; No [ ]; ? [ ] Method: [ e. g. OECD, other ( with the year of publication or updated of the method used)] < text> 31 Urea ( CAS # 57 13 6) GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea Remarks: < text> References: Tchounwou, P. B., Englande, A. J., and Malek, E. A. 1991. Arch. of Environmental Contamination and Toxicology 21 pp. 359 364.

* 4.3 TOXICITY TO AQUATIC PLANTS, e. g. algae Species: Scenedesmus quadrigauda green algae Endpoint: Biomass [ ]; Growth rate [ ]; Other [ X] Exposure period: 72 hr Results: Toxicity threshold ( TT) ( 192 hr): > 10,000 mg/ l. EC50 ( h) = < text> mg/ L NOEC = < text> mg/ L LOEC = < text> mg/ L Analytical monitoring: Yes [ ]; No [ ]; ? [ ] Method: [ e. g. OECD, other ( with the year of publication or updated of the method used)] Cell multiplication inhibition test Open system [ ]; Closed system [ ] GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea Remarks: < text> References: Bringmann, G. und Kühn, R. 1978. Vom Waser 50. pp. 45 60.

4.4 TOXICITY TO BACTERIA ( Single species test and tests on overall processes such as nitrification or soil respiration are included in this item.)

( a) Type: Aquatic [ ]; Field [ ]; Soil [ ]; Other [ ] Species: Pseudomonas putida Exposure period: 16 hr Results: Toxicity Threshold ( TT) 16 hr: > 10,000 mg/ l Analytical monitoring: Yes [ ]; No [ ]; ? [ ] Method: [ e. g. OECD, other ( with the year of publication or updated of the method used)] < text> GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea Remarks: < text> References: Bringmann, G. and Kühn, R. 1980. Water Research 14, pp. 231 241.

( b) Type: Aquatic [ X]; Field [ ]; Soil [ ]; Other [ ] 32 Urea ( CAS # 57 13 6) Species: Microcystis aeruginosa ( blue green algae) Exposure period: 192 hr Results: Toxicity Threshold ( TT) 192 hr: 47 mg/ l Analytical monitoring: Yes [ ]; No [ ]; ? [ ] Method: [ e. g. OECD, other ( with the year of publication or updated of the method used)] Cell multiplication inhibition test GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea Remarks: < text> References: Bringmann, G. and Kühn, R. 1978. Vom Wasser 50, pp. 45 60.

( c) Type: Aquatic [ ]; Field [ ]; Soil [ ]; Other [ X] Species: Photobacterium luminescence Exposure period: 5 minutes Results: EC50 ( 5 min): 24,000 mg/ l Analytical monitoring: Yes [ ]; No [ ]; ? [ ] Method: [ e. g. OECD, other ( with the year of publication or updated of the method used)] Microtox assay GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea Remarks: < text> References: Bulich, A. A., Greene, M. W., and Isenberg, D. L. Reliability of bacterial luminescence assay for determination of the toxicity of pure compounds and complex effluents. pp. 338 347; in Branson & Dickson ( eds.) Aquatic Toxicology and Hazard Assessment: 4th conference, ASTM STP 737; Philadelphia.

4.5 CHRONIC TOXICITY TO AQUATIC ORGANISMS 4.5.1 CHRONIC TOXICITY TO FISH ( Effects on reproduction, embryo/ larva, etc.)

Type of test: Static [ ]; Semi static [ ]; Flow through [ ]; Other ( e. g. field test) [ ] Open system [ ]; Closed system [ ] Species: Talapia mossambica Endpoint: Length of fish [ ]; Weight of fish [ ]; Reproduction rate [ ]; Other [ X] feeding and growth Exposure period: 25 days Results: See remarks EC50 ( d) = < text> mg/ L Not reported NOEC = < text> mg/ L Not reported LOEC = < text> mg/ L Not reported Analytical monitoring: Yes [ ]; No [ ]; ? [ ] 33 Urea ( CAS # 57 13 6) Method: [ e. g. OECD, other ( with the year of publication or updated of the method used)] < text> GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea, purity: < text> Remarks: decrease in feeding and growth rates with increasing concentration ( 5,000 10,000,  15,000 20,000 mg/ L) References: Planichamy, S., Wilram, S., and Arunachalam, S. 1985. Sublethal effects of urea on food intake, growth and conversion in Tilapia mossambica. Environment and Ecology, Vol. 3, No. 2, pp 157 161.

(*) 4.5.2 CHRONIC TOXICITY TO AQUATIC INVERTEBRATES ( e. g. Daphnia reproduction. The need to conduct tests for this endpoint will depend inter alia upon possible concern for long term effects.)

Type of test: Static [ ]; Semi static [ ]; Flow through [ ]; Other ( e. g. field test) [ ] Open system [ ]; Closed system [ ] Species: < text> Endpoint: Mortality [ ]; Reproduction rate [ ]; Other [ ] Exposure period: < text> Results: < text> EC50 ( d) = < text> mg/ L NOEC = < text> mg/ L LOEC = < text> mg/ L Analytical monitoring: Yes [ ]; No [ ]; ? [ ] Method: [ e. g. OECD, other ( with the year of publication or updated of the method used)] < text> GLP: Yes [ ] No [ ] ? [ ] Test substance: < text>, purity: < text> Remarks: < text> References: < text>

4.6 TOXICITY TO TERRESTRIAL ORGANISMS 4.6.1 TOXICITY TO SOIL DWELLING ORGANISMS Type of test: Artificial Soil [ ]; Filter Paper [ ]; Other [ X] Sandy loam soil Species: Grassland earthworms ( Oligochaeta, Lumbricidae) Endpoint: Mortality [ ]; Weight [ ]; Other [ X] Numbers and biomass Exposure period: < text> Results: LC50 ( at 7 and 14 days for earthworms) 34 Urea ( CAS # 57 13 6) Application of nitrogenous fertilizers to grassland for long period may have a deletrious effect on earthworms in the absence of liming. Analytical monitoring: Yes [ ]; No [ ]; ? [ ] Method: [ e. g. OECD, other ( with the year of publication or updated of the method used)] Sandy loam soil. Organic matter 6.2   6.7%. Fertilizer was organic coated urea, the organic coating being based on soybean oil at annual rate 60, 120 and 180 kg N/ ha. Soil was treated annually for 20 years. GLP: Yes [ ] No [ ] ? [ ] Test substance: < text>, purity: < text> Remarks: < text> References: Wei Chun Ma, L., Brussaard, L., and DeRidder, J. A. 1990. Agriculture and Environment 30, pp. 71 80.

4.6.2 TOXICITY TO TERRESTRIAL PLANTS Species: Glycine max ( L.) Merr, soybean Endpoint: Emergence [ ]; Growth [ ]; Other [ X] Exposure period: 7 days Results: Leaf tip necrosis observed after foliar fertilization of soybeans with urea Method: [ e. g. OECD, other ( with the year of publication or updated of the method used)] Exposure to 9 mg urea/ leaf GLP: Yes [ ] No [ X] ?[ ] Test substance: Urea Remarks: It was concluded in this study that necrosis resulted from accumulation of toxic amounts of urea rather than from formation of toxic amounts of ammonia. References: Krogmeir, J. M., McCarthy, G. W., and Bremner, J. M. 1989. Proc. Natl. Acad. Sci. USA Vol. 86. pp. 8189 8191.

4.6.3 TOXICITY TO OTHER NON MAMMALIAN TERRESTRIAL SPECIES ( INCLUDING AVIAN)

Species: Pigeon Endpoint: Mortality [ ]; Reproduction rate [ ]; Weight [ ]; Other [ ] Exposure period: < text> Results: LDLO: 16,000 mg/ kg subcutaneous LD50 ( acute), LC50 ( subacute) Method: [ e. g. OECD, other ( with the year of publication or updated of the method used)] < text> GLP: Yes [ ] No [ X] ? [ ] Test substance: Urea 35 Urea ( CAS # 57 13 6) Remarks: < text> References: FDA, PB 288673. 1978. Evaluation of the Health Aspects of Urea as a Food Ingredient.

4.7 BIOLOGICAL EFFECTS MONITORING ( INCLUDING BIOMAGNIFICATION) [ Studies on variation of predominant species in certain ecosystems ( e. g. mesocosm) and monitoring of biological effects are included.]

Results: Substance: Nitrogenous fertilizers Species or ecosystem studied: Soil properties after long term fertilization with urea Effects monitored: Soil pH and micronutrients availabilities Results: 20 years of urea fertilization reduced soil pH significantly, compared with the control area. The soil acidification occurs due to nitrification NH4+ which is decomposition product of urea. Urea fertilization caused also an increase in micronutrients ( Fe, Cu, Mn) and a decrease in available P and exchangeable bases ( Ca, Mg, Na). Chemical analysis: mg/ kg Fe Cu Mn Ca Mg Na metres 0.06 0.1 urea 75.7 2.12 51.2 2566 478 15 no urea 52.8 1.63 14.8 2949 548 25 metres 0.21 0.29 urea 45.4 1.99 15.6 3666 719 42 no urea 44.7 1.94 8.9 3893 822 71 Remarks: [ Information on environmental conditions ( e. g. water characteristics; suspended matter, pH, temperature, hardness; soil/ sediment characteristics: % organic matter, clay content.] Soil acidification occurred also on areas treated with ammonia, NH4NO3 and urea NH4NO3 mixture. The annual rate of N/ ha was 105  224 kg and corn ( Zea mays L.), grain sorghum ( Sorghum bicolor), winter wheat ( Triticum aestivum L.) and soybean ( Glycine max L.) were planted. References: Darusman, L. R., et al. 1991. Soil Sci. Soc. Am. J. 55: pp. 1097 1100.

4.8 BIOTRANSFORMATION AND KINETICS ( Under this item, studies on absorption, distribution, metabolism and excretion etc. should be given.) 36 Urea ( CAS # 57 13 6) Type: Animal [ ]; Aquatic [ ]; Plant [ ]; Terrestrial [ ]; Other [ ] Results: < text> Remarks: Ammonia is toxic to all vertebrates. It can be converted to the less toxic urea, but this is a metabolically expensive process found only in terrestrial vertebrates that cannot readily excrete ammonia and marine fish that use urea as osmotic filler. Freshwater fish mostly excrete ammonia with only a small quantity of urea. Urea is the end product of biochemical protein decomposition and the main component of mammalian urine. References: Randall, D. J., Wood, C. M., Perry, S. F., Bergman, H., Maloiy, G. M. O., Mommsen, T. P., and Wright, P. A. 1989. Urea excretion as a strategy for survival in a fish living in a very alkaline environment. Nature 337 ( 12) pp. 165 166. Harper, H. A. and Rodwell, V. W. 1977. Review of Physiological Chemistry, 16th ed., Lange Medical Publications, Los Altos California. p. 625.

4.9 ADDITIONAL REMARKS Results: < text> Remarks: < text> References: < text>

5. TOXICITY ( Where observations on humans are available, these should be entered in the appropriate " comments" section or under section 5.11.)

* 5.1 ACUTE TOXICITY 5.1.1 ACUTE ORAL TOXICITY ( a) Type: LD0 [ ]; LD100 [ ]; LD50 [ ]; LDL0 [ ]; Other [ ] Species/ strain: Rat/ strain not mentioned Mouse/ strain not mentioned Value: LD50 or other measure of acute toxicity ( e. g., in case fixed dose test): 1. LD50: 14,300 mg/ kg orl rat male 2. LD50: 15,000 mg/ kg orl rat female 1. LD50: 11,500 mg/ kg orl mouse male 2. LD50: 13,000 mg/ kg orl mouse female 37 Urea ( CAS # 57 13 6) Other data: LD50 values to mammals in non oral exposure: 1. LD50: 9,400 mg/ kg scu rat male 1. LD50: 8,200 mg/ kg scu rat female 2. LD50: 9,200 mg/ kg scu mouse male 2. LD50: 10,700 mg/ kg scu mouse female 1. LD50: 5,400 mg/ kg ivn rat male 1. LD50: 5,300 mg/ kg ivn rat female 2. LD50: 4,600 mg/ kg ivn mouse male 2. LD50: 5,200 mg/ kg ivn mouse female Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] Not known GLP: Yes [ ] No [ X] ? [ ] Test substance: Urea Remarks: The general symptoms consisting mainly of sedation, loss of righting reflex and staggering gait were noted in both rats and mice. References: Sato, N. et al., OY Yakari ( Pharmacometrics Tokyo) 13. 1978. pp. 749 772.

( b) Type: LD0 [ ]; LD100 [ ]; LD50 [ ]; LDL0 [ ]; Other [ ] Species/ strain: 1. Cattle ( cow)/ strain not mentioned 2. Sheep/ strain not mentioned 3. Pony/ strain not mentioned 4. Rabbit/ strain not mentioned 5. Dog/ strain not mentioned 6. Frog/ strain not mentioned 7. Pigeon/ strain not mentioned 8. Guinea pig/ strain not mentioned Value: LD50 or other measure of acute toxicity ( e. g., in case fixed dose test): 1. LD50: 510mg/ kg orl cattle 1. LD50: 600 1,080 mg/ kg orl cattle 1. LDLO: 116 mg/ kg orl cattle 2. LD50: 510 mg/ kg orl sheep 2. LDLO: 160 mg/ kg orl sheep 3. LDLO: 3,310 3,610 mg/ kg orl pony 4. LDLO: 5,000 mg/ kg orl rabbit Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] Detailed information of the test methods was not available at time of the evaluation. GLP: Yes [ ] No [ X] ? [ ] Test substance: Urea Remarks: References: FDA, PB 288673. 1978. Evaluation of the Health Aspects of Urea as a Food Ingredient. 38 Urea ( CAS # 57 13 6) ( c) Type: LD0 [ ]; LD100 [ ]; LD50 [ ]; LDL0 [ ]; Other [ ] Species/ strain: Ruminants Value: LD50 or other measure of acute toxicity ( e. g., in case fixed dose test): Urea can cause clinical signs of toxicosis in ruminants at 300  500 mg/ kg body wt and death at 1000  1500 mg/ kg body wt. Horses are less susceptible, urea being lethal at approximately 4000 mg/ kg body wt. Monogastric animals, such as swine and baby calves, are not affected by urea or biuret except for a mild diuretic action. Discriminating dose: < text> Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] Not specified GLP: Yes [ ] No [ X] ? [ ] Test substance: Urea Remarks: References: Oehme, F. W. and Barrel, D. S. 1986. Veterinary Gastrointestinal Toxicology, Chapter 17; in Rozman K. and Hänninen O. ( eds.). Gastrointestinal Toxicology, Elsevier Science Publishers, Amsterdam. pp. 489 490.

( d) Type: LD 0 [ ]; LD100 [ ]; LD50 [ ]; LDL0 [ ]; Other [ ] Species/ strain: Young pigs ( 3) Value: LDLO: > 16,000 mg/ kg oral pig Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] GLP: Yes [ ] No [ X] ? [ ] Test substance: Urea, purity: < text> Remarks: Ten percent ( m/ m) urea in pig food over a period of 5 days was without apparent deleterious effects. References: Button, J. P. et al. 1982. Journal of the South African Veterinary Association, 53 No. 1, pp. 67 68.

5.1.2 ACUTE INHALATION TOXICITY Type: LC0 [ ]; LC100 [ ]; LC50 [ ]; LCL0 [ ]; Other [ ] Species/ strain: Not specified Exposure period: < text> Value: 22 mg/ m3 dermal and respiratory/ mucous membrane  mild irritation Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] < text> GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea, dust Remarks: < text> 39 Urea ( CAS # 57 13 6) References: National Safety Council. UREA: Safe Use and Handling. Data Sheet 1 691, Rev. 90.

5.1.3 ACUTE DERMAL TOXICITY Type: LD0 [ ]; LD100 [ ]; LD50 [ ]; LDL0 [ ]; Other [ ] Species/ strain: < text> Value: < text> Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] < text> GLP: Yes [ ] No [ ] ? [ ] Test substance: < text>, purity: < text> Remarks: < text> References: < text>

5.1.4 ACUTE TOXICITY BY OTHER ROUTES OF ADMINISTRATION ( e. g. subcutaneous, intravenous, etc.)

Type: LC0 [ ]; LC100 [ ]; LC50 [ ]; LCL0 [ ]; LD0 [ ]; LD100 [ ]; LD50 [ ]; LDL0 [ ]; Other [ ] Species/ strain: < text> Route of Administration: i. m. [ ]; i. p. [ ]; i. v. [ ]; Infusion [ ]; s. c. [ ]; Other [ ] Exposure period: < text> Value: < text> mg/ kg b. w. Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] < text> GLP: Yes [ ] No [ ] ? [ ] Test substance: < text>, purity: < text> Remarks: < text> References: < text>

5.2 CORROSIVENESS/ IRRITATION 5.2.1 SKIN IRRITATION/ CORROSION ( a) Species/ strain: Human skin Results: Highly corrosive [ ]; Corrosive [ ]; Highly irritating [ ]; Irritating [ ]; Moderately irritating [ ]; Slightly irritating [ ]; Not irritating [ ] Test results: give maximum scores after 72 hrs. for scarified human skin: 7.5% urea ( in water)   slight irritancy 30% urea ( in water)   marked irritancy 40 Urea ( CAS # 57 13 6) Aquacare HP 10% urea   slight irritancy Classification: ( if possible, according to EC Directive 67/ 548/ EEC) Highly corrosive ( causes severe burns) [ ]; Corrosive ( causes burns) [ ]; Irritating [ ]; Not irritating [ ] Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] Chamber Scarification Test GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea; 7.5%, 30% solutions in water Aquacare HP  10% urea ( Allergan) Remarks: Other data: Comparison between hypo and hyperreactive individuals with 30% urea in water after 48 hrs: Individual type Scarified skin Normal Skin Hyporeactors 0.8 = slight 0 = no irritancy Hyperreactors 2.4 = moderate 0 = no irritancy References: Frosch, P. J. and Kligman, A. M. 1977. The Chamber Scarification Test for Assessing Irritancy to Topically Applied Substances; in Drill, V. A. and Lazar, P., ( eds.) Cutaneous Toxicity, Academic Press Inc., New York. pp. 127 153.

( b) Species/ strain: Human skin Results: Highly corrosive [ ]; Corrosive [ ]; Highly irritating [ ]; Irritating [ ]; Moderately irritating [ ]; Slightly irritating [ ]; Not irritating [ X] Classification: ( if possible, according to EC Directive 67/ 548/ EEC) Highly corrosive ( causes severe burns) [ ]; Corrosive ( causes burns) [ ]; Irritating [ ]; Not irritating [ ] Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] Not specified GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea, 10% water solution Remarks: 24 hour exposure References: Alchangian, L. V., et at. 1986. Vestn. Dermatol. Venerol. 9, pp. 26 29.

( c) Species/ strain: Male nude mouse/ MF1 h Results: Highly corrosive [ ]; Corrosive [ ]; Highly irritating [ ]; Irritating [ ]; Moderately irritating [ ]; Slightly irritating [ ]; Not irritating [ X] Classification: ( if possible, according to EC Directive 67/ 548/ EEC) Highly corrosive ( causes severe burns) [ ]; Corrosive ( causes burns) [ ]; Irritating [ ]; Not irritating [ ] Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] Others GLP: Yes [ ] No [ ] ? [ X] 41 Urea ( CAS # 57 13 6) Test substance: Urea, 10% water solution Remarks: 10% urea induced no discernible change in the histological appearance of the skin. References: Lashmar, U. T., et al. 1989. J. Pharm. Pharmacol. 41: 118 121.

( d) Species/ strain: Rabbit/ strain not mentioned Results: Highly corrosive [ ]; Corrosive [ ]; Highly irritating [ ]; Irritating [ ]; Moderately irritating [ ]; Slightly irritating [ ]; Not irritating [ X] Classification: ( if possible, according to EC Directive 67/ 548/ EEC) Highly corrosive ( causes severe burns) [ ]; Corrosive ( causes burns) [ ]; Irritating [ ]; Not irritating [ ] Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] 20 hrs. semiocclusive application of 50% urea water solution on the back and ear skin of rabbit. GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea, 50% water solution Remarks: The original report of the study was not available for the Finnish expert group at the time of the evaluation. References: BASF AG, Abteilung Toxikologie, internal study ( I/ 140), unpublished; as cited in BASF AG, AIDA.

5.2.2 EYE IRRITATION/ CORROSION Species/ strain: Rabbit/ strain not mentioned Results: Highly corrosive [ ]; Corrosive [ ]; Highly irritating [ ]; Irritating [ ]; Moderately irritating [ ]; Slightly irritating [ ]; Not irritating [ X] Classification: ( if possible, according to EC Directive 67/ 548/ EEC) Irritating [ ]; Not irritating [ ]; Risk of serious damage to eyes [ ] Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] OECD 405 GLP: Yes [ X] No [ ] ? [ ] Test substance: Urea Remarks: The original report of the study was not available for the Finnish scientific expert group at the time of the evaluation. References: BASF AG, Abteilung Toxikologie, internal study ( 88/ 207), unpublished; as cited in BASF AG, AIDA.

5.3 SKIN SENSITIZATION Type: < text> Species/ strain: Human skin 42 Urea ( CAS # 57 13 6) Results: Sensitizing [ ]; Not sensitizing [ X]; Ambiguous [ ] Classification: ( if possible, according to EC Directive 67/ 548/ EEC) Sensitizing [ ]; Not sensitizing [ X] Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] Not specified GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea, 10% water solution Remarks: < text> References: Alchangian, L. V., et al. 1986. Vestn. Dermatol. Venerol 9: 26 29.

* 5.4 REPEATED DOSE TOXICITY ( a) Species/ strain: Rat/ Wistar Sex: Female [ ]; Male [ ]; Male/ Female [ ]; No Data [ X] Route of Administration: Dermal Exposure period: 4 weeks Frequency of treatment: < text> Post exposure observation period: < text> Dose: 10%, 20% and 40% in ointment Control group: Yes [ ]; No [ ]; No Data [ ] Concurrent no treatment [ ]; Concurrent vehicle [ ]; Historical [ ] NOEL: < text> LOEL: < text> Results: No dose dependent toxicity was observed. There were no consistent treatment related effects on standard haematological parameters, clinical chemistry, organ weights or organ histopathology, including the testicles, prostate, seminal vesicles, ovaries and the uterus. Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] Substance was applied to the back skin ( 20 cm2) during 4 weeks. GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea Remarks: References: Sato, N. et al. 1977. Toxicological studies of urea. Acute, subacute and chronic test in rats and mice. Oyo Yakuri ( Pharmacometrics Tokyo) 13: 749 772.

( b) Species/ strain: Rat/ Wistar Sex: Female [ ]; Male [ ]; Male/ Female [ ]; No Data [ X] Route of Administration: Dermal Exposure period: 24 weeks Frequency of treatment: < text> Post exposure observation period: < text> 43 Urea ( CAS # 57 13 6) Dose: 10%, 20% and 40% in ointment Control group: Yes [ ]; No [ ]; No Data [ ] Concurrent no treatment [ ]; Concurrent vehicle [ ]; Historical [ ] NOEL: < text> LOEL: < text> Results: There were no consistent treatment related effects on standard haematological parameters, clinical chemistry or different organs. Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] The substance was applied to the back skin ( 20 cm) during 24 weeks. GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea Remarks: References: Sato, N. et al. 1977. Toxicological studies of urea. Acute, subacute and chronic test in rats and mice. Oyo Yakuri ( Pharmacometrics Tokyo) 13: 749 772.

( c) Species/ strain: Rat/ not known Sex: Female [ ]; Male [ ]; Male/ Female [ ]; No Data [ X] Route of Administration: Oral Exposure period: 190 days Frequency of treatment: < text> Post exposure observation period: < text> Dose: 2000 25,000 mg/ kg/ day in fodder Control group: Yes [ ]; No [ ]; No Data [ ] Concurrent no treatment [ ]; Concurrent vehicle [ ]; Historical [ ] NOEL: < text> LOEL: < text> Results: 250,000 ppm and 200,000 ppm were lethal in 12 days and 20 76 days, respectively. There was weight loss and suppression of sexual function at lower doses. Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] Repeated dosing for 190 days, 20,000 250,000 ppm ( about 2000 25000 mg/ kg/ day) in fodder. GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea, purity not known Remarks: The validity of the study is limited by the small number of animals used ( often 1 to 3 per group) and failure to report actual food intake. Extreme weight loss of the rats suggests that inanition was likely. References: FDA, PB 288673. 1978. Evaluation of the Health Aspects of Urea as a Food Ingredient.

( d) Species/ strain: Dog/ not known 44 Urea ( CAS # 57 13 6) Sex: Female [ ]; Male [ ]; Male/ Female [ ]; No Data [ X] Route of Administration: Subcutaneous Exposure period: 45 days Frequency of treatment: Every 8 hours Post exposure observation period: < text> Dose: 3,000 to 4,000 mg/ kg Control group: Yes [ ]; No [ ]; No Data [ ] Concurrent no treatment [ ]; Concurrent vehicle [ ]; Historical [ ] NOEL: < text> LOEL: < text> Results: Plasma urea levels were 200 to 700 mg/ 100 ml. The treatment caused mild drowsiness and increased diuresis in animals but did not affect hematocrit, platelet counts nor EEG. Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] Urea was injected subcutaneously every 8 hours into 12 unilaterally nephrectomized dogs for 45 days. GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea Remarks: < text> References: FDA, PB 288673. 1978. Evaluation of the Health Aspects of Urea as a Food Ingredient.

* 5.5 GENETIC TOXICITY IN VITRO A. Bacterial Test ( a) Type: ( e. g. Bacterial reverse mutation assay, Bacterial gene mutation study, Cytogenetic Assay etc.) Bacterial gene mutation study System of testing: Ames assay Concentration: < text> Metabolic activation: With [ ]; Without [ ]; With and Without [ X]; No Data [ ] Results: Cytotoxicity conc: < text> < text> Precipitation conc: < text> Genotoxic effects: + ?  With metabolic activation: [ ] [ ] [ X] Without metabolic activation: [ ] [ ] [ X] Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] Ames test GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea, purity unknown Remarks: < text> 45 Urea ( CAS # 57 13 6) References: Ishidate, M., Sofuni, T., and Yoshikawa, K. 1981. Chromosomal aberration tests in vitro as a primary screening tool for environmental mutagens and/ or carcinogens. GANN Monograph on Cancer Research 27: 95 108.

( b) Type: ( e. g. Bacterial reverse mutation assay, Bacterial gene mutation study, Cytogenetic Assay etc.) Bacterial gene mutation study System of testing: Ames assay Concentration: 5 5,000  g/ plate Metabolic activation: With [ ]; Without [ ]; With and Without [ X]; No Data [ ] Results: Cytotoxicity conc: With metabolic activation: < text> Without metabolic activation: < text> Precipitation conc: < text> Genotoxic effects: + ?  With metabolic activation: [ ] [ ] [ X] Without metabolic activation: [ ] [ ] [ X] Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] Ames test GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea, 99% pure, dissolved in water Remarks: Negative results at a dose range of 5 5000 µ g/ plate. References: Shimizu, H., Suzuki, Y., Takemura, N., Goto, S., and Matsushita, H. 1985. The results of microbial mutation test for forty three industrial chemicals. Jpn. J. Ind. Health 27: 400 419.

( c) Type: ( e. g. Bacterial reverse mutation assay, Bacterial gene mutation study, Cytogenetic Assay etc.) Bacterial gene mutation study System of testing: Ames assay Concentration: < text> Metabolic activation: With [ ]; Without [ ]; With and Without [ X]; No Data [ ] Results: Cytotoxicity conc: With metabolic activation: < text> Without metabolic activation: < text> Precipitation conc: < text> Genotoxic effects: + ?  With metabolic activation: [ ] [ ] [ X] Without metabolic activation: [ ] [ ] [ X] Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] Ames test GLP: Yes [ ] No [ ] ? [ X] 46 Urea ( CAS # 57 13 6) Test substance: Urea, 99% pure, dissolved in DMSO Remarks: Negative results at a dose range of 100 10000 ug/ plate with and without metabolic activation with rat liver and hamster liver S9 mix. References: Mortelmans, K., Haworth, S., Lawler, T., Speck, W., Tainer, B., and Zeiger, E. 1986. Salmonella mutagenicity tests: II. Results from the testing of 270 chemicals. Env. Mutag. 8, Suppl. 7, pp. 1 119.

B. Non bacterial in vitro test ( a) Type: ( e. g. mammalian cell gene mutation assay, cytogenetic assay etc.) Cytogenetic Assay System of testing: Chinese hamster fibroblast ( CHL) Concentration: < text> Metabolic activation: With [ ]; Without [ X]; With and Without [ ]; No Data [ ] Results: Cytotoxicity conc: With metabolic activation: < text> Without metabolic activation: < text> Precipitation conc: < text> Genotoxic effects: + ?  With metabolic activation: [ ] [ ] [ ] Without metabolic activation: [ X] [ ] [ ] Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] Chromosomal aberration test GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea, purity unknown, dissolved in physiological saline Remarks: Aberrations in 37% of metaphases at 24 h ( chromosomal gaps, chromatid or chromosomal breaks, translocations, fragmentation). The maximally effective concentration was 266 mM, a very high concentration suggesting a low clastogenic potential. References: Ishidate, M. and Odashima, S. 1977. Chromosome test with 134 compounds on Chinese hamster cells in vitro  a screening for chemical carcinogens. Mut. Res. 48: 337 354.

( b) Type: ( e. g. mammalian cell gene mutation assay, cytogenetic assay etc.) Cytogenetic Assay System of testing: Chinese hamster fibroblast ( CHL) Concentration: < text> Metabolic activation: With [ ]; Without [ X]; With and Without [ ]; No Data [ ] Results: Cytotoxicity conc: With metabolic activation: < text> 47 Urea ( CAS # 57 13 6) Without metabolic activation: < text> Precipitation conc: < text> Genotoxic effects: + ?  With metabolic activation: [ ] [ ] [ ] Without metabolic activation: [ X] [ ] [ ] Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] Chromosomal aberration test GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea, purity unknown Remarks: Chromosomal aberrations detected in 20% of metaphases at urea concentration of 13 g/ l ( 216 mM), indicating a low clastogenic potential. References: Ishidate, M., Sofuni, T., and Yoshikawa, K. 1981. Chromosomal aberration tests in vitro as a primary screening tool for environmental mutagens and/ or carcinogens. GANN Monograph on Cancer Research. 27: 95 108.

( c) Type: ( e. g. mammalian cell gene mutation assay, cytogenetic assay etc.) Mammalian cell gene mutation assay System of testing: Mouse lymphoma Concentration: < text> Metabolic activation: With [ ]; Without [ X]; With and Without [ ]; No Data [ ] Results: Cytotoxicity conc: With metabolic activation: < text> Without metabolic activation: < text> Precipitation conc: < text> Genotoxic effects: + ?  With metabolic activation: [ ] [ ] [ ] Without metabolic activation: [ X] [ ] [ ] Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] Mouse lymphoma TK locus assay GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea, laboratory grade Remarks: Weakly positive at very high urea concentrations 530 662 mM, negative at 132 mM, equivocal at 265 397 mM. Authors discuss the possibility that the positive genotoxic findings may depend on secondary cellular effects ( e. g., difference in osmotic pressure across the cell membrane) at high concentration which might not take place under in vivo conditions. References: Wangenheim, J. and Bolcsfoldi, G. 1988. Mouse lymphoma L5178Y thymidine kinase locus assay of 50 compounds. Mutagenesis 3: 193 205. 48 Urea ( CAS # 57 13 6) ( d) Type: ( e. g. mammalian cell gene mutation assay, cytogenetic assay etc.) Cytogenetic Assay System of testing: Rat hepatocytes Concentration: < text> Metabolic activation: With [ X]; Without [ ]; With and Without [ ]; No Data [ ] Results: Cytotoxicity conc: With metabolic activation: < text> Without metabolic activation: < text> Precipitation conc: < text> Genotoxic effects: + ?  With metabolic activation: [ ] [ ] [ X] Without metabolic activation: [ ] [ ] [ ] Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] Analysis for DNA singlestrand breaks by alkaline elution. GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea, laboratory grade, dissolved in water Remarks: Negative ( 0.3 3mM) References: Sina, J. F., Bean, C. L., et al. 1984. Evaluation of the alkaline elution/ rat hepatocyte assay as a predictor of carcinogenic/ mutagenic potential. Mut. Res. 1132: 357 391.

( e) Type: ( e. g. mammalian cell gene mutation assay, cytogenetic assay etc.) Mammalian cell gene mutation assay System of testing: Mouse lymphoma L5178Y/ TK+/ Concentration: < text> Metabolic activation: With [ ]; Without [ X]; With and Without [ ]; No Data [ ] Results: Cytotoxicity conc: With metabolic activation: < text> Without metabolic activation: < text> Precipitation conc: < text> Genotoxic effects: + ?  With metabolic activation: [ ] [ ] [ ] Without metabolic activation: [ X] [ ] [ ] Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] Analysis for DNA signlestrand breaks by unwinding and hydroxyapatite elution GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea, laboratory grade Remarks: Positive at very high concentrations 628 and 718 mM with relative fractions of ssDNA of 9.2 and 17.3%, respectively. Although a dose response was found, 49 Urea ( CAS # 57 13 6) lower urea concentrations ( 359 539 mM) did not yield responses classified as positive. References: Garberg, P., Åkerblom, E L., and Bolcsfoldi, G. 1988. Evaluation of genotoxicity test measuring DNA strand breaks in mouse lymphoma cells by alkaline unwinding and hydroxyapatite elution. Mut. Res. 203: 155 176.

* 5.6 GENETIC TOXICITY IN VIVO ( a) Type: ( e. g. mammalian cell gene mutation assay, cytogenetic assay etc.) Cytogenetic Assay System of testing: Mouse/ Swiss albino Concentration: < text> Metabolic activation: With [ ]; Without [ ]; With and Without [ ]; No Data [ ] Results: Cytotoxicity conc: With metabolic activation: < text> Without metabolic activation: < text> Precipitation conc: < text> Genotoxic effects: + ?  With metabolic activation: [ ] [ ] [ ] Without metabolic activation: [ X] [ ] [ ] Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] Bone marrow cytogenetic test GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea, purity unknown Remarks: Bone marrow cell metaphases from mice fed with urea 500 mg per animal per day in food for 5 days ( dosage approaching an acutely lethal dose) exhibited chromosome breaks, acentric fragments, translocations, gaps and constrictions at a 7 fold rate compared to controls. The interpretation of this clastogenic effect is limited by the usage of a single extremely high dose level. References: Chaurasia, O. P. and Sinna, S. P. 1987. Effects of urea on mitotic chromosomes of mice and onion. Cytologia 52: 877 882.

5.7 CARCINOGENICITY ( a) Species/ strain: Mouse/ C57B1/ 6 Sex: Female [ ]; Male [ ]; Male/ Female [ X]; No Data [ ] Route of Administration: diet Exposure period: > 12 months 50 Urea ( CAS # 57 13 6) Frequency of treatment: < text> Post exposure observation period: 4 months Doses: 0.45%, 0.9%, 4.5% in diet Control group: Yes [ ]; No [ ]; No Data [ ] Concurrent no treatment [ ]; Concurrent vehicle [ ]; Historical [ ] Results: Not carcinogenic Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] Chronic toxicity and carcinogenicity screening study over 12 months GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea Remarks: Five animals per sex from all dose groups were necropsied at the end of the treatment period, and the gonads were histologically examined. No pathology was reported. After further 4 months of follow up, all survivors were killed, necropsied and the tissues were fixed. However, concerning the reproductive organs histological tumor data on the ovary and the uterus only were given. Other sex organs may not have been histologically studied. References: Fleischman, R. W., et al. 1980. J. Environmental Pathology & Toxicology 3, ( 5/ 6), pp. 149 170.

( b) Species/ strain: Rat/ Fischer 344 Sex: Female [ ]; Male [ ]; Male/ Female [ X]; No Data [ ] Route of Administration: Diet Exposure period: > 12 months Frequency of treatment: < text> Post exposure observation period: 4 months Doses: 0.45%, 0.9%, 4.5% Control group: Yes [ ]; No [ ]; No Data [ ] Concurrent no treatment [ ]; Concurrent vehicle [ ]; Historical [ ] Results: Not carcinogenic Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] Chronic toxicity and carcinogenicity screening study over 12 months GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea Remarks: Five animals per sex from all dose groups were necropsied at the end of the treatment period, and the gonads were histologically examined. No pathology was reported. After further 4 months of follow up all survivors were killed, necropsied and the tissues were fixed. The testes, prostate and uterus were histologically examined for the occurrence of tumors. Although there was a statistically increased incidence of interstitial cell 51 Urea ( CAS # 57 13 6) adenomas of the testis in the high dose group, its biological significance was deemed questionable, since the lesion may occur in 100% of controls. References: Fleischman, R. W., et al. 1980. J. Environmental Pathology & Toxicology 3, ( 5/ 6), pp. 149 170.

5.8 TOXICITY TO REPRODUCTION Type: Fertility [ ]; One generation study [ ]; Two generation study [ ]; Other [ X] Species/ strain: < text> Sex: Female [ ]; Male [ ]; Male/ Female [ ]; No Data [ ] Route of Administration: < text> Exposure period: < text> Frequency of treatment: < text> Post exposure observation period: < text> Duration of the test < text> Doses: < text> Control group: Yes [ ]; No [ ]; No Data [ ] Concurrent no treatment [ ]; Concurrent vehicle [ ]; Historical [ ] NOEL Parental: < text> NOEL F1 Offspring: < text> NOEL F2 Offspring: < text> Results: < text> General parental toxicity: < text> Toxicity to offspring: ( weights of litter, postnatal growth, viability, etc.) < text> Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] < text> GLP: Yes [ ] No [ ] ? [ ] Test substance: < text>, purity: < text> Remarks: Based on the carcinogenicity screening studies with mice and rats and repeated dose toxicity studies by dermal route with rats, where no toxic effects were observed in the gonads, even after histopathological examination, and the lack of evidence for developmental toxicity in limited mouse and rat studies, urea would not be expected to display significant potential for reproductive toxicity. References: < text>

* 5.9 DEVELOPMENTAL TOXICITY/ TERATOGENICITY ( a) Species/ strain: Mouse/ ICR 52 Urea ( CAS # 57 13 6) Sex: Female [ X]; Male [ ]; Male/ Female [ ]; No Data [ ] Route of Administration: Oral Duration of the test: < text> Exposure period: Single dose Frequency of treatment: < text> Doses: 2,000 mg/ kg Control group: Yes [ ]; No [ ]; No Data [ ] Concurrent no treatment [ ]; Concurrent vehicle [ ]; Historical [ ] NOEL Maternal Toxicity: < text> NOEL teratogenicity: < text> Results: Not teratogenic Maternal general toxicity: not toxic Pregnancy/ litter data: < text> Fetal data: No effects Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] A single oral dose study GLP: Yes [ ] No [ X] ? [ ] Test substance: Urea Remarks: A single dose, 2000 mg/ kg was administered orally to 10 pregnant mice on day 10 of pregnancy. Not an adequate teratogenicity study. References: Teramoto, et al. 1981. Teratology 23: 335 342.

( b) Species/ strain: Rat/ Wistar Sex: Female [ X]; Male [ ]; Male/ Female [ ]; No Data [ ] Route of Administration: Oral Duration of the test: < text> Exposure period: Single oral dose Frequency of treatment: < text> Doses: 2,000 mg/ kg Control group: Yes [ ]; No [ ]; No Data [ ] Concurrent no treatment [ ]; Concurrent vehicle [ ]; Historical [ ] NOEL Maternal Toxicity: < text> NOEL teratogenicity: < text> Results: Not teratogenic Maternal general toxicity: Not toxic Pregnancy/ litter data: < text> Fetal data: < text> Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] A single oral dose study GLP: Yes [ ] No [ X] ? [ ] Test substance: Urea Remarks: A single dose, 2000 mg/ kg was administered orally only to 4 pregnant rats on day 12 of pregnancy. Not an adequate teratogenicity study. References: Teramoto, et al. 1981. Teratology 23: 335 342. 53 Urea ( CAS # 57 13 6) ( c) Species/ strain: Rat/ Wistar Sex: Female [ X]; Male [ ]; Male/ Female [ ]; No Data [ ] Route of Administration: Gavage Duration of the test: < text> Exposure period: 14 days Frequency of treatment: 2 dose, 12 hours aparat Doses: 50 g/ kg/ day Control group: Yes [ ]; No [ ]; No Data [ ] Concurrent no treatment [ ]; Concurrent vehicle [ ]; Historical [ ] NOEL Maternal Toxicity: < text> NOEL teratogenicity: < text> Results: Blood urea levels ranged from about 1000 mg/ 100 ml at one hour after administration to 100 mg/ 100 ml before the next dose ( 12 h later). No hypertrophy or other kidney changes were detected nor were any teratogenic effects noted. Maternal general toxicity: < text> Pregnancy/ litter data: < text> Fetal data: < text> Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] Urea in water was given in 2 doses 12 h apart by gavage to 6 rats during pregnancy for an average of 14 days and the dams were allowed to deliver. Within 48 hours the pups were killed and the kidneys examined. GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea Remarks: Not a full range teratogenicity study. References: Seipelt, H., Zoellner, K., Hilgenfeld, E., and Grossman, H. 1969. Untersuchungen an Niereg neugeborener Ratten nach chronischer Harnstoffapplikation beim Muttertier. Zschr Urol 62: 623 627.

( d) Species/ strain: Chick embryo Sex: Female [ ]; Male [ ]; Male/ Female [ ]; No Data [ ] Route of Administration: Injection Duration of the test: < text> Exposure period: 7th   20th hour of incubation Frequency of treatment: Once Doses: 50 900 mg Control group: Yes [ ]; No [ ]; No Data [ ] Concurrent no treatment [ ]; Concurrent vehicle [ ]; Historical [ ] NOEL Maternal Toxicity: < text> NOEL teratogenicity: < text> Results: Among 132 embryos 78 showed neural, vascular or cardiac abnormalities. 54 Urea ( CAS # 57 13 6) Maternal general toxicity: < text> Pregnancy/ litter data: < text> Fetal data: < text> Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] Fifty to 900 mg urea dissolved in egg albumin was injected into eggs between 7th and 20th hour of incubation. GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea Remarks: The results indicate that urea was teratogenic in chick embryo. References: FDA, PB 288673. 1978. Evaluation of the Health Aspects of Urea as a Food Ingredient.

( e) Species/ strain: Chick embryo Sex: Female [ ]; Male [ ]; Male/ Female [ ]; No Data [ ] Route of Administration: Injection Duration of the test: < text> Exposure period: < text> Frequency of treatment: Once Doses: 200, 400, 800 and 1,200 mg/ kg Control group: Yes [ X]; No [ ]; No Data [ ] Concurrent no treatment [ ]; Concurrent vehicle [ ]; Historical [ ] NOEL Maternal Toxicity: < text> NOEL teratogenicity: < text> Results: Mortality of the embryos varied 8.8 38.9% dose  dependently. The mortality in the control group was 6.1%. In the treated embryos, the plasma T3 level increased and T4 level decreased. Electron microscopy revealed cytoplasmic oedema, mitochondrial swelling and membrane damage in thyroid cells. Maternal general toxicity: < text> Pregnancy/ litter data: < text> Fetal data: < text> Method: [ e. g. OECD, other ( with the year of publication or updating of the method used)] Urea was injected in a volume of 0.05 ml distilled water into the air sack of the egg on day 16, 17 and 18, respectively, of incubation. GLP: Yes [ ] No [ ] ? [ X] Test substance: Urea of p. a. grade Remarks: The results indicate that urea was foetotoxic to the chicken. References: Mora, S., Simon, F., and Kapp, P. 1991. Toxicological model investigation on chicken embryo. Acta Vet Scand. Suppl. 87: 197 198. 55 Urea ( CAS # 57 13 6) 5.10 OTHER RELEVANT INFORMATION A. Specific toxicities Type: ( e. g. neurotoxicity, immunotoxicity, etc.) Oncogenic transformation < text> Results: < text> Remarks: In a BALB/ c 3T3 cell transformation assay, urea gave a negative result at a dose range 2.5 20 mg/ ml. Reference: Rundell, J. O., Guntakatta, M., and Matthews, E. J. 1983. Criterion development for the application of BALB/ c 3T3 cells to routine Environ. Sci. Res. 27: 309 324.

B. Toxicodynamics, toxicokinetics Type: ( e. g. neurotoxicity, immunotoxicity, etc.) < text> Results: Ruminants Urea is generally regarded a safe and efficient feed additive ( substitute for natural proteins) for ruminants. The toxicity on urea depends on the formation of ammonia. Problems occur when ingested urea releases more ammonia than the rumen microorganisms can fully utilize to sythetize amino acids and protein. Urea can cause clinical toxicosis in ruminants at 0.3 0.5 g/ kg body weight and death at 1 1.5 g/ kg. Horses are less susceptible. Monogastic animals, such as swine and baby calves, are not affected by urea except for a mild diuretic action. Humans Urea penetrates rapidly into the human stratum corneum; penetration is enhanced at higher urea concentrations and with time. However, transport to systemic circulation is slow and limited. About 5.9% of urea applied to human skin was recovered in the urine. Urea is extremely soluble in water and is adsorbed and distributed rapidly after oral doses. In man, the peak concentration in blood is attained in 30 to 90 minutes after a peroral dose. The dose 30 g of urea ( about 0.5 g/ kg) doubles serum urea levels in 20 min and a maximum level of 94.6 mg/ 100 ml is achieved in 90 minutes ( mean control 36 mg/ 100 ml). Urea is an endogenous product of protein and aminoacid catabolism in mammals. The physiological concentration of urea in human blood is 3.3  6.7 mmol/ l ( 200 400 mg/ l) and the diurnal excretion in urine of humans is 20 35 g. 56 Urea ( CAS # 57 13 6) Rats Subcutaneous ingestion of urea to pregnant rats showed that the substance readily penetrated the placenta and raised fetal urea concentrations. The development of urea cycle enzymes occurs at a later period in the rat fetus. Remarks: Oehme, F. W. and Barrett, D. S. 1986. Veterinary gastrointestinal toxicology In: Gastrointestinal Toxicology. K. Rozman and O. Hänninen, editors. Elsevier Science Publishers pp. 464 513. Wohlrab, W. and Hassler, N. 1981. Penetrationskinetik von Harnstoff in die menschliche Haut. Dermatol. Mon. Schr. 167: 277 283. Wohlrab, W. 1988. Welche harnstoffkonzentration is für die externe Therapie notwendiz? Dermatol. Mon. Schr. 174: 94 98. Harper, H. A. and Rodwell, V. W. 1977. Review of Physiological Chemistry, 16th ed., Lange Medical Publications, Los Altos, California p. 625 Altman, P. L. and Dittmer, D. S. 1974. Biology Data Book, Vol. III, 2nd ed. Federation of American Societies for Experimental Biology pp. 1494 & 1501. FDA, PB 288673. 1978. Evaluation of the Health Aspects of Urea as a Food Ingredient. Wohlrab, W. and Schiemann, S. 1976. Untersuchungen zum Mechanisms der Harnstoffwirkung auf die Haut. Arch. Derm. Res. 255: 23 30. Feldman, R. and Maibach, H. I. 1970. Absorption of some organic compounds through the skin in man. J. Invest. Dermatol. 54: 399 404.

* 5.11 EXPERIENCE WITH HUMAN EXPOSURE [ Describe information on workplace exposure such as concentration of chemicals in the workplace or indoor environment ( manufacturing, maintenance and professional use), number of workers ( in ranges for each situation), frequency and duration of exposure, if available. In addition, enter details of effects of accidental or occupational exposure, epidemiological and clinical studies, case reports, etc.]

Results: Remarks: Urea is widely used at 10% and lower concentrations in clinical dermatology as a keratolytic agent; it hydrates the skin, inhibits epidermal proliferation and possesses antipruritic and antibacterial properties. At higher than 10% concentration urea may be irritating to the skin. Urea has been extensively used during the last two decades in the treatment of dry skin, both clinically and in cosmetic products. No long term side effects have been found. No reports of contact allergy were located and, in spite of common use for many years, no epidermal or dermal atrophy has been reported. 57 Urea ( CAS # 57 13 6) Intra amniotic infusion of hypertonic ( e. g., 30%) urea solution has been clinically used for the termination of midtrimester pregnancy. Urea is used in therapeutic ointments and creams. Urea concentration range is 40 120 mg/ g in medical products marketed in Finland. Urea has been used intravenously as an osmotic diuretic in treatment of oliguria following burns, surgery or trauma; in promoting diuresis following prostatectomy. It has also shown to be effective in status epilecticus ( usual intravenous infusion, 100 mg to 1 g/ kg daily, as 35% solution in dextrose injection rate not exceeding 4 ml/ min). Other dose information: It is usually administered orally as a single dose of 20 g taken 2 5 times daily. A female patient with an idiopathic syndrome of inappropriate secretion of antidiuretic hormone ( SIADH) was successfully treated for more than 5 years without any side effects with oral urea ( 30 g/ day) allowing her a normal fluid intake ( 1 1.5 1/ day). Urea is used less commonly than other osmotic agents to reduce intraocular pressure and vitreous volume prior to iridectomy and other ocular surgical procedures. Helicobacter pylori ( H. pylori) is currently known as an important cause of chronic active gastritis and peptic ulceration. H. pylori has an extremely high urease activity. Ammonia generated by hydrolysis of urea is deleterious to the gastric mucosa. Reference: Müller, K. H. 1979. Pflugshaupt Ch. Harnstoff in der Dermatologie I ( Review). Zbl. Haut 142: 157 168. Greenhalf, J. O. and Diggory, P. L. C. 1971. Induction of therapeutic abortion by intra amniotic injection of urea. Br. Med. J. 1: 28 29. Greenhalft, J. O. 1972. Termination of pregnancy during mid trimester by intra amniotic injection of urea. Br. J. Clin. Pract. 26: 24 26. Anteby, S. O., Segal, S., and Polishuk, W. Z. 1974. Termination of midtrimester pregnancy by intraamniotic injection of urea. Obstet. Gynecol. 43: 765 768. Burkman, R. T., Bell, W. R., Atienza, M. F. and King, T. M. 1977. Coagulopathy with midtrimester induced abortion: Association with hyperosmolar urea administration. Am. J. Obstet. Gynecol. 127: 533 536. Registry of the Medical Products Marketed in Finland, National Agency for Welfare and Health, May 1992. Osol, A., Hoover, J. E., et al. ( eds.). 1975. Remington's Pharmaceutical Sciences, 15th ed. Easton Pennsylvania: Mark Publishing Co. p. 864, as cited in HSDB 1991. American Medical Association, AMA Department of Drugs, AMA Drug Evaluations, 3rd ed. 1977. Littleton, 58 Urea ( CAS # 57 13 6) Massachusetts: PSG Publishing Co. Inc. p. 936; as cited in HSDB 1991. Swanbeck, G. 1992. Urea in treatment of dry skin. Acta Derm Venereal ( Stockh) Suppl. 177: 7 8. Stüttgen, G. 1992. Ergebnisse und Konsequenzen eirer langfristigen Harnstofftherapie für die medizinische Praxis. Hautarzt, Suppl. 11: 9 12. Decaux G., Prospect, F., Penninckx, R., Namias, B., and Soupart, A. 1993. 5 Year treatment of the chronic syndrome of inappropriate secretion of ADH with oral urea. Nephron 63: 468 470. Saita, H., et al. 1992. Helicobacter pylori has an ulcerogenic action in the ischemic stomach of rats. J. Clin. Gastroenterol 14 ( Suppl. 1): S122 S126. 59 Urea ( CAS # 57 13 6) 6. REFERENCES Alchangian, L. V., et at. 1986. Vestn. Dermatol. Venerol. 9, pp. 26 29.

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