Fluorouracil. TOXNET profile from Hazardous Substances Data Base.

FLUORIDE ACTION NETWORK PESTICIDE PROJECT

Fluorouracil. TOXNET profile from Hazardous Substances Data Base.

See for Updates: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB

FLUOROURACIL
CASRN: 51-21-8
For other data, click on the Table of Contents

Human Health Effects:

Evidence for Carcinogenicity:

Inadequate evidence of carcinogenicity in humans. Inadequate evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer,1972-PRESENT. (Multivolume work).,p. S7 63 (1987)]**PEER REVIEWED**

Human Toxicity Excerpts:

EARLIEST UNTOWARD SYMPTOMS DURING COURSE OF THERAPY ARE ANOREXIA & NAUSEA; THESE ARE FOLLOWED BY STOMATITIS & DIARRHEA.
[Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. 1230]**PEER REVIEWED**

OCCURRENCE OF ... LESIONS IN STOMA OF COLOSTOMIES & @ POST-MORTEM EXAM OF GI TRACT, AS WELL AS COMPLAINTS OF DYSPHAGIA, RETROSTERNAL BURNING, & PROCTITIS, INDICATES THAT ENTERIC INJURY MAY OCCUR @ ANY LEVEL.
[Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. 1276]**PEER REVIEWED**

MAJOR TOXIC EFFECTS ... RESULT FROM MYELOSUPPRESSIVE ACTION. NADIR OF LEUKOPENIA IS USUALLY BETWEEN 9TH & 14TH DAY AFTER 1ST INJECTION OF DRUG. THROMBOCYTOPENIA & ANEMIA MAY ALSO OCCUR.
[Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. 1230]**PEER REVIEWED**

LOSS OF HAIR, OCCASIONALLY PROGRESSING TO TOTAL ALOPECIA, NAIL CHANGES, DERMATITIS, & INCR PIGMENTATION & ATROPHY OF SKIN MAY BE ENCOUNTERED. NEUROLOGICAL MANIFESTATIONS INCLUDING HAVE BEEN REPORTED, & MYELOPATHY HAS BEEN OBSERVED AFTER INTRATHECAL ADMIN OF FLUOROURACIL.
[Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. 1230]**PEER REVIEWED**

APHTHOUS ULCERATION MAY OCCUR ... OTHER TOXIC EFFECTS INCL ... HYPERPIGMENTATION, PHARYNGITIS, ESOPHAGITIS, CEREBELLAR ATAXIA, & EPISTAXIS. LASSITUDE & ASTHENIA, LASTING FROM 12-36 HR AFTER INJECTION, MAY OCCUR. WHEN ... DEATH /OCCURS/ IT IS USUALLY FROM SEPTICEMIA ... TOPICALLY, /IT/ ... MAY INDUCE PHOTOSENSITIZATION ... .
[Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1079]**PEER REVIEWED**

PRURITIS & IRRITATION ARE MOST COMMON ADVERSE REACTIONS. INTENSE BURNING PAIN IS REPORTED OCCASIONALLY.
[American Medical Association. AMA Drug Evaluations Annual 1991. Chicago, IL: American Medical Association, 1991. 1047]**PEER REVIEWED**

IN ONE INSTANCE SOLN CONTAINING 50 MG/ML ACCIDENTALLY SPRAYED INTO EYES OF PHYSICIAN. AFTER 3-5 MIN EYES WERE THOROUGHLY IRRIGATED WITH WATER. NO SIGNIFICANT REACTION OCCURRED EXCEPT SLIGHT ITCHING & TRANSIENT HYPEREMIA DURING NEXT 24 HR. SUBSEQUENT OPHTHALMOLOGIC EXAM SHOWED NO SIGNIFICANT ABNORMALITY.
[Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 501]**PEER REVIEWED**

Continuous ambulatory ECG monitoring was performed on 25 patients (41 to 79 yr, mean age = 60 + or - 2) undergoing 5-fluorouracil (5-FU) infusion (4 to 5 g/sq m, 96 to 120 hr) for treatment of solid tumors (squamous cell carcinomas of the head and neck). Patients were monitored for 23 + or - 4 hr before 5-FU infusion, and 98 + or - 9 hr during 5-FU infusion. 7 Patients received 5-FU alone, 14 patients received a combination of 5-FU and cisplatin, and 4 patients received combination of 5-FU and carboplatin. Anginal episodes were rare only one patient had angina (during 5-FU infusion). However, asymptomatic ST changes ( > or = 1 mm ST deviation) were common: 6/25 patients (24%) had ST changes before 5-FU infusion vs 17 (68%) during 5-FU infusion (p < 0.002). The incidence of ischemic episodes/patient/hr was 0.05 + or - 0.02 prior to 5-FU infusion vs 0.13 + or - 0.03 during 5-FU infusion (p < 0.001); the duration of ECG changes was 0.6 + or - 0.3 min/patient/hr before 5-FU vs 1.9 + or - 0.5 min/patient/hr during 5-FU (p < 0.01). ECG changes were more common among patient with known coronary artery disease. There were cases of sudden death, both of which occurred at the end of the chemotherapy course. Follow up of the group for 7 mo did not reveal further cardiac events.
[Rezkalla S et al; J Clin Oncol 7 (4): 509-14 (1989)]**PEER REVIEWED**

60 women with metastatic breast cancer refractory to at least one chemotherapeutic regimen were treated with fluorouracil (FU, 250, 300, 370, or 400 mg/sq m/day) and high dose continuous infusion folinic acid (leucovorin calcium, 500 mg/sq m/day). Therapy consisted of a 6 day infusion of leucovorin calcium initiated 24 hr before a 5 day course of FU given iv. The mean dose of FU admin was 304 mg/sq m/day. 1 complete remission lasting 8.7 mo and partial remissions ranging in duration from 1.3 to 12.8 mo were observed, for an objective response rate of 17% (95% confidence interval for response, 8% to 27%). 9/10 responding patient had metastatic disease that had objectively progressed on previous chemotherapy with a FU containing regimen. This program was well tolerated, with toxicities consisting mainly of stomatitis and granulocytopenia.
[Doroshow JH et al; J Clin Oncol 7 (4): 439-44 (1989)]**PEER REVIEWED**

179 patients with advanced measurable colorectal cancer not previously treated with chemotherapy were studied in a randomized clinical trial to compare 2 schedules of delivery for single agent fluorouracil (5-FU). The standard treatment was a daily 500 mg/sq m bolus dose admin iv for 5 consecutive days and repeated at 5 wk intervals. Investigational treatment was a continuous infusion of 5-FU admin 24 hr/day for a dose of 300 mg/sq m/day for 10 wk or more. Both treatments were continued until the development of disease progression or unless interrupted for toxicity. With continuous treatment, dosage was reduced to 250 mg and then 50 mg/kg/day if significant toxicity occurred. Using stringent objective criteria requiring independent confirmation of x-ray or scan documented response, the tumor response rate reached 7% (6/87) for the bolus arm and 30% (26/87) for the infusion arms. Toxicity was substantially different for the 2 arms with major leukopenia observed only on the bolus arm, 22% developing grade 3 (severe) or grade 4 (life-threatening) leukopenia with 4 sepsis-related deaths. Stomatitis, was also observed more commonly on the bolus arm; 13% bolus vs 4% infusional pt experienced severe or worse stomatitis. Hand foot syndrome was observed only in the infusional arm, requiring treatment interruptions and dose reductions in 24% of pt, but with little impact on quality of life. Overall survival for the 2 groups was comparable (median = 11.2 mo for bolus vs 10.3 mo for infusion).
[Lokich JJ et al; J Clin Oncol 7 (4): 425-32 (1989)]**PEER REVIEWED**

Major toxicity: Mucositis, which may have a high mortality if bloody diarrhea occurs; myelosupression.
[Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990. 980]**PEER REVIEWED**

Systemic administration of fluorouracil has also had adverse effects on the lids, lacrimal system and eyes, producing excessive tearing and discomfort from obstruction of the lacrimal system, from ectropion of the lower lids, or from blepharoconjunctivitis. Fortunately, there has been a strong tendency to recover from these side effects when fluorouracil has been discontinued.
[Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 440]**PEER REVIEWED**

... Human glaucomatous eyes of types notoriously prone to failure similarly had subconjunctival injections of 3 to 5 mg of /fluorouracil/ once or twice daily for 2 weeks after standard filtering surgery. Complications, occurring in nearly half of the eyes, consisted of corneal epithelial defects and leakage from conjunctival wounds or needle tracts, but most healed in a few days to 2 weeks from the end of fluorouracil treatment, and encouraging results were obtained in reducing intraocular pressure by formation of the desired filtration blebs. No problems with the lacrimal system and no cicatricial entropion was encountered in this series, and no systemic complications.
[Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 441]**PEER REVIEWED**

Five percent 5-fluorouracil, an antineoplastic agent, is often applied to the lower genital tract in the treatment of vaginal and vulvar human papillomavirus infections. Little is known regarding possible teratogenic effects from its topical use in pregnancy. Five cases of antenatal lower genital tract 5-fluorouracil use were correlated with pregnancy outcome. Topical 5-fluorouracil was applied up to 16 weeks gestation. Intravaginal doses ranged from 1 to 2.5 g; one patient applied 5-fluorouracil to the vulva. Antenatal ultrasound performed on four patients did not show any fetal structural abnormalities. One patient underwent antenatal genetic amniocentesis that detected a 47,XXX complement of chromosomes. All the pregnancies continued without complications and with subsequent term delivery of healthy infants. The unwitting vaginal and vulvar use of 5-fluorouracil i pregnancy did not result in significant morbidity or mortality
[Van Le L et al; J Reprod Med 36 (12): 872-4 (1991)]**PEER REVIEWED**

Drug Warnings:

GREAT CARE SHOULD BE TAKEN TO PREVENT INHALING PARTICLES OF FLUOROURACIL & EXPOSING SKIN TO IT.
[Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1079]**PEER REVIEWED**

... ANOREXIA & NAUSEA ... STOMATITIS & DIARRHEA ... CONSTITUTE RELIABLE WARNING SIGNS THAT SUFFICIENT DOSE HAS BEEN ADMIN.
[Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. 1230]**PEER REVIEWED**

DRUG IS QUITE TOXIC, ABOUT 2/3 OF PT SHOWING SIGNS OF TOXICITY; MORTALITY RATE IS ABOUT 3% WHEN TREATMENT IS INITIATED BY DAILY DOSES.
[Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1079]**PEER REVIEWED**

HEALING PROCESS MAY CONTINUE ... AFTER THERAPY IS STOPPED ... ACTINIC KERATOSES MAY EVENTUALLY RECUR. ... PATIENTS SHOULD BE INFORMED OF THAT INFLAMMATION, PRURITIS, PROLONGED DISCOLORATION OF SKIN, & THAT BURNING SENSATION MAY DEVELOP.
[American Medical Association. AMA Drug Evaluations Annual 1991. Chicago, IL: American Medical Association, 1991. 1047]**PEER REVIEWED**

IF THERE IS EXCESSIVE INFLAMATION OF NORMAL SKIN, TREATMENT SHOULD BE DISCONTINUED. ... SHOULD BE APPLIED WITH CARE TO SENSITIVE AREAS (EG, AROUND EYES, NASOLABIAL FOLDS) IF THERE IS EXCESSIVE INFLAMMATORY RESPONSE ON NORMAL SKIN TREATMENT SHOULD BE DISCONTINUED. EXPOSURE TO SUNLIGHT DURING & FOR 1-2 MO FOLLOWING TREATMENT SHOULD BE MINIMIZED.
[American Medical Association, AMA Department of Drugs, AMA Drug Evaluations. 3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977. 910]**PEER REVIEWED**

LOW THERAPEUTIC INDICES OF THESE AGENTS EMPHASIZE NEED FOR SKILLFUL SUPERVISION BY PHYSICIANS FAMILIAR WITH ACTION OF FLUORINATED PYRIMIDINES & POSSIBLE HAZARDS OF CHEMOTHERAPY.
[Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. 1276]**PEER REVIEWED**

PATIENTS WITH COMPROMISED BONE MARROW FUNCTION AS RESULT OF PREVIOUS THERAPY EITHER WITH ALKYLATING AGENTS OR X-RAY TO PELVIS OR VERTEBRAE ARE PARTICULARLY SENSITIVE TO MYELOSUPPRESSIVE ACTION ... .
[Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. 1229]**PEER REVIEWED**

IN PT WITH EXTENSIVE LIVER METASTASES, CATABOLISM OF DRUG MAY BE MARKEDLY IMPAIRED & THERAPY MAY BE CONTRAINDICATED; IF TREATMENT IS INSTITUTED, REDUCED DOSES MUST BE ADMIN TO PREVENT HAZARDS OF OVERDOSAGE.
[Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. 1276]**PEER REVIEWED**

... PALLIATION IS SEEN IN ONLY 20% OF PT WITH COLONIC CARCINOMA & 10-15% WITH RECTAL CARCINOMA. PALLIATION OCCURS IN ABOUT 40% OF CASES OF CARCINOMA OF BREAST.
[Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1079]**PEER REVIEWED**

If intractable vomiting occurs, fluorouracil should be immediately discontinued. Patients should be questioned and the mouth examined daily for early evidence of stomatitis. Appearance of stomatitis, as evidenced by either oral mucosal erythema or ulceration at the inner margin of the lips, or of esophagopharyngitis as evidenced by a sore throat or dysphagia, necessitates cessation of therapy. Diarrhea necessitates immediate discontinuance of the drug. GI ulceration or bleeding, or hemorrhage at any site, also requires prompt cessation of treatment.
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 576]**PEER REVIEWED**

Since leucovorin calcium enhances the toxicity of fluorouracil, combined leucovorin and fluorouracil therapy should be used with extreme caution in geriatric or debilitated patients since such patients are more likely to develop serious toxicity from fluorouracil.
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 576]**PEER REVIEWED**

Leukocyte counts with differential should be made before each dose of fluorouracil is given and if the leukocyte count falls to below 3500/cu mm or decreases rapidly, or if there is a fall in the platelet count to below 100,000/cu mm, the drug should be discontinued. If the leukocyte count drops to less than 2000/cu mm, the patient should be placed in protective isolation and appropriate measures taken for the prevention of infection.
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 576]**PEER REVIEWED**

Patients in poor nutritional state, or whose bone marrow is depressed by previous therapy or by infiltration of malignant cells, are more likely to develop serious toxicity from fluorouracil than are patients in relatively good condition. Fluorouracil should be used with extreme caution in patients who have previously received high-dose pelvic irradiation therapy or alkylating agents and in patients with impaired liver or kidney function. The drug should also be used with extreme caution in patients with widespread metastatic involvement of the bone marrow.
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 576]**PEER REVIEWED**

Safety and efficacy of fluorouracil in children have not been established.
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 576]**PEER REVIEWED**

Although there is no evidence to date of teratogenicity caused by fluorouracil in humans, other drugs that inhibit DNA synthesis (eg, methotrexate) have been reported to be teratogenic in humans. In addition, drugs that inhibit DNA, RNA, and protein synthesis like fluorouracil might be expected to have adverse effects on perinatal and postnatal development. There are no adequate and controlled studies using fluorouracil in pregnant women, and the drug should be used during pregnancy only in life threatening situations or severe disease for which safer drugs cannot be used or are ineffective. Women of childbearing potential should be advised to avoid becoming pregnant during fluorouracil therapy. If the drug is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 576]**PEER REVIEWED**

It is not known whether fluorouracil is distributed into milk. Because fluorouracil inhibits DNA, RNA, and protein synthesis, it is recommended that women not nurse an infant while receiving the drug.
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 576]**PEER REVIEWED**

POTENTIAL ADVERSE EFFECTS ON FETUS: Exposure in first trimester resulted in skeletal abnormalities; hypoplasia of aorta, lungs, thymus, and gastrointestinal tract; and urinary tract abnormalities. Fetus exposed in third trimester had cyanosis and clonus. No adverse effects reported from topical use. POTENTIAL SIDE EFFECTS ON BREAST-FED INFANT: Not known whether excreted, but breast-feeding not recommended. FDA Category: D (D = There is evidence of human fetal risk, but the potential benefits from use in pregnant women may be acceptable despite the potential risks (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective.)) /from Table II/
[Stockton, D.L. and A.S. Paller. J Am Acad Dermatol 23 (1):87-103 (1990)]**QC REVIEWED**

Emergency Medical Treatment:

EMT Copyright Disclaimer:

Portions of the POISINDEX(R) database are provided here for general reference. THE COMPLETE POISINDEX(R) DATABASE, AVAILABLE FROM MICROMEDEX, SHOULD BE CONSULTED FOR ASSISTANCE IN THE DIAGNOSIS OR TREATMENT OF SPECIFIC CASES. Copyright 1974-1998 Micromedex, Inc. Denver, Colorado. All Rights Reserved. Any duplication, replication or redistribution of all or part of the POISINDEX(R) database is a violation of Micromedex' copyrights and is strictly prohibited.
The following Overview, *** FLUOROURACIL ***, is relevant for this HSDB record chemical.

Life Support:

o This overview assumes that basic life support measures have been instituted.

Clinical Effects:

SUMMARY OF EXPOSURE 0.2.1.1 ACUTE EXPOSURE o Management of 5-fluorouracil overdose is supportive. o Expect to see similar toxic effects as those reported in the literature for therapeutic dosing regimens, but experience with new high-dose antineoplastic protocols may reveal unpredicted toxicity. o The earliest adverse reactions to fluorouracil are anorexia and nausea. These are followed shortly after by stomatitis and diarrhea. Stomatitis may be preceded by a sensation of dryness, followed by erythema and formation of a white, patchy membrane that develops into ulceration and necrosis. o Major toxic effects result from myelosuppressive action. Clinical effects are leukopenia, thrombocytopenia, and anemia. Loss of hair, occasionally progressing to total alopecia, nail changes, dermatitis, and increased pigmentation and atrophy of skin may occur. o Less common severe effects include neurologic toxicity (mental status changes, ataxia, and neuropathy), cardiogenic shock, and gastrointestinal bleeding and perforation. o Dose-limiting toxicities with capecitabine therapy may include gastrointestinal effects (nausea, vomiting, diarrhea, abdominal pain), fatigue, dizziness, thrombocytopenia, and palmar-plantar erythrodysesthesia. VITAL SIGNS 0.2.3.1 ACUTE EXPOSURE o Tachycardia and hypotension have been reported with therapeutic use of 5-FU. Fever has occurred during capecitabine clinical trials. HEENT 0.2.4.1 ACUTE EXPOSURE o Visual disturbances and lacrimation may occur. CARDIOVASCULAR 0.2.5.1 ACUTE EXPOSURE o Chest pain, tachycardia and ECG changes have been reported. Cardiac enzymes may be normal or elevated. Hypotension may be noted. RESPIRATORY 0.2.6.1 ACUTE EXPOSURE o Pulmonary edema may occur. NEUROLOGIC 0.2.7.1 ACUTE EXPOSURE o Acute cerebellar syndrome may occur following 5-FU administration. o Capecitabine therapy may cause paresthesias, fatigue, and vertigo/dizziness. GASTROINTESTINAL 0.2.8.1 ACUTE EXPOSURE o Nausea, vomiting, diarrhea stomatitis, and anorexia are frequently reported with therapeutic doses of 5-FU and capecitabine. Abdominal pain, GI ulceration or perforation with bleeding may occur less frequently with 5-FU or capecitabine therapy. Paralytic ileus has been reported in serious overdoses of 5-FU. HEPATIC 0.2.9.1 ACUTE EXPOSURE o Hepatic and biliary tract disease may occur. o Cholecystitis, sclerosing cholangitis, hepatitis, biliary sclerosis and fatal liver cirrhosis may follow therapeutic doses of 5-FU. o Hepatic failure was reported following chronic administration of tegafur, a prodrug of 5-fluorouracil. HEMATOLOGIC 0.2.13.1 ACUTE EXPOSURE o Delayed bone marrow depression should be expected and peak effects occur at about 7 to 14 days post-exposure. DERMATOLOGIC 0.2.14.1 ACUTE EXPOSURE o Alopecia may be a delayed toxicity. Hyperpigmentation may occur. Palmar-plantar erythrodysesthesia syndrome (dose dependent) occurs with high-dose, prolonged infusions of fluorouracil (over 300 mg per square meter of body surface area per day) and with capecitabine therapy. MUSCULOSKELETAL 0.2.15.1 ACUTE EXPOSURE o Rhabdomyolysis may occur. IMMUNOLOGIC 0.2.19.1 ACUTE EXPOSURE o Hypersensitivity reactions have been reported. REPRODUCTIVE HAZARDS o Fluorouracil is known to be teratogenic in animals, as well as causing degenerative effects in male test animals' reproductive system. CARCINOGENICITY 0.2.21.1 IARC CATEGORY o IARC (Fluorouracil) (RTECS, 2001) 1. Animal: Inadequate evidence 2. Human: Inadequate evidence 3. Group 3 0.2.21.2 HUMAN OVERVIEW o The carcinogenicity of the agent is undetermined. GENOTOXICITY o DNA damage, unscheduled DNA synthesis and DNA inhibition were observed in humans as well as test animals. Mutations were also noted in human and animal cells. Chromosomal aberrations detected by cytogenetic analysis, sister chromatid exchange and gene conversion/mitotic recombination have been noted in mammalian cells as well as microorganisms (RTECS, 2001).

Laboratory:

o Blood parameters should be monitored for bone marrow depression, bleeding tendency and infection. o Monitor fluid and electrolyte depletion in symptomatic patients.

Treatment Overview:

ORAL EXPOSURE o GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in Trendelenburg and left lateral decubitus position or by endotracheal intubation. Control any seizures first. 1. CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion. o ACTIVATED CHARCOAL: Administer charcoal as slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old. o Bone marrow toxicity should be monitored. Monitor patient for bleeding tendency and infection. Septicemia may be a fatal complication. o Monitor electrolytes for possible electrolyte depletion due to vomiting and diarrhea. o Allopurinol may reduce the dose-limiting toxicity of high-dose 5-FU. o Uridine rescue is being studied in humans to reduce the toxicity associated with high-dose regimens of 5-FU. o Extravasation requires no specific treatment. INHALATION EXPOSURE o INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with beta2 agonist and corticosteroid aerosols. EYE EXPOSURE o DECONTAMINATION: Irrigate exposed eyes with copious amounts of tepid water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist, the patient should be seen in a health care facility. DERMAL EXPOSURE o DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water. A physician may need to examine the area if irritation or pain persists.

Range of Toxicity:

o The therapeutic dose of 5-fluorouracil varies widely. Experienced oncologists are using high-dose regimens as well as treating some GI tumors with oral 5-FU.

[Rumack BH: POISINDEX(R) Information System. Micromedex, Inc., Englewood, CO, 2001; CCIS Volume 110, edition exp November, 2001. Hall AH & Rumack BH (Eds):TOMES(R) Information System. Micromedex, Inc., Englewood, CO, 2001; CCIS Volume 110, edition exp November, 2001.] **PEER REVIEWED**

Animal Toxicity Studies:

Evidence for Carcinogenicity:

Non-Human Toxicity Excerpts:

5-Fluorouracil was tested for mutagenicity in the Salmonella/microsome preincubation assay using a protocol approved by the National Toxicology Program. 5-Fluorouracil was tested over a wide range of doses (0, 0.03, 0.1, 0.3, 1.0, 2.0, and 3.3 ug/plate) in four Salmonella typhimurium strains (TA98, TA100, TA1535, and TA1537) in the presence and absence of Aroclor induced rat or hamster liver S9. 5-Fluorouracil was negative in these tests and the highest ineffective dose level tested in any Salmonella tester strain was 1.0 ug/plate. Data for the 2.0 and 3.3 ug/plate dose levels were not reported for all test conditions, and those that were, caused slight clearing of the background lawn.
[Zeiger E et al; Environ Mutagen 9: 1-110 (1987)]**PEER REVIEWED**

The Drosophila wing somatic mutation and recombination test was applied to a series of chemicals to determine its suitability in genotoxicity screening. In the acute feeding series a concentration of 5 mM of fluorouracil was given for 6 hours and resulted in positive induction of all three types of spots. In contrast, chronic feeding with the comparatively low concentration of 0.1 mM is effective in inducing small single spots only. For the large single and the twin spots the results were inconclusive in the chronic exposure.
[Graf U et al; Mutat Res 222 (4): 359-73 (1989)]**PEER REVIEWED**

The cytostatic agent 5-fluorouracil (1X10-5, 10-7 and 10-9 mg/ml) was tested in the initiator tRNA acceptance assay for carcinogens (ie, in the presence of microsomal enzymes and NADPH) in the presence of 2 concn of microsomal enzymes. Treatment of tRNA resulted in a 26% inhibition of its acceptance of L-methionine.
[Hradec J et al; Carcinogenesis 10 (8): 1413-7 (1989)]**PEER REVIEWED**

Fluorouracil has been shown to be mutagenic in some but not all strains of Salmonella typhimurium and in Saccharomyces cerevisiae. In addition, the drug was mutagenic in the micronucleus test on mouse bone marrow cells and, at very high concentrations, produced chromosomal breaks in hamster fibroblasts in vitro. ...
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 576]**PEER REVIEWED**

Long-term studies in animals to determine the carcinogenic potential of fluorouracil have not been performed; however, no evidence of carcinogenicity was observed in several animal studies following oral or iv administration of the drug for up to 1 year. In vitro, the drug has induced oncogenic transformation of fibroblasts from mouse embryo.
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 576]**PEER REVIEWED**

The drug has not been studied in animals for potential effects on perinatal and postnatal development; however, it does cross the placenta in rats and has caused increased resorptions and embryolethality in rats. In monkeys, doses greater than 40 mg/kg resulted in abortion of all embryos exposed to the drug.
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 576]**PEER REVIEWED**

Fluorouracil has not been adequately studied in animals to determine its effects on fertility and general reproductive performance. Following intraperitoneal administration of 125 or 250 mg/kg in rats, chromosomal aberrations and changes in chromosomal organization of spermatogonia were induced; spermatogonial differentiation was also inhibited, resulting in transient infertility. In a strain of mouse that is sensitive to the induction of sperm head abnormalities after exposure to a number of chemical mutagens and carcinogens, no abnormalities were produced at oral dosages of up to 80 mg/kg daily. Following intraperitoneal administration at weekly doses of 25 or 50 mg/kg weekly for 3 weeks during the preovulatory phases of oogenesis in female rat, the incidence of fertile matings was substantially reduced, development of preimplantation and postimplantation embryos was delayed, and the incidence of preimplantation lethality and chromosomal anomalies in the embryos was increased. In a limited study in rabbits, a single 25 mg/kg dose or daily doses of 5 mg/kg for 5 days had no effect on ovulation, appeared not to affect implantation, and had only a limited effect in producing zygote destruction. Drugs that inhibit DNA, RNA, and protein synthesis like fluorouracil might be expected to have adverse effects on gametogenesis.
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 576]**PEER REVIEWED**

ALTHOUGH IT HAS BEEN SHOWN THAT FLUOROURACIL IS MUCH MORE LETHAL TO LOGARITHMICALLY GROWING CELLS THAN TO STATIONARY CELLS, THERE IS NO CLEARLY DEMONSTRATED EFFECT @ DEFINITE STAGE OF CELL CYCLE.
[Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. 1228]**PEER REVIEWED**

The previous experiment showed that treatment with a teratogenic dose of 5-fluorouracil increased the expressivity of the Os gene and, in turn, Os gene decreased 5-fluorouracil induced postaxial oligodactyly. The present experiment was designed to examine a possible interaction of Os gene and subteratogenic dose of 5-fluorouracil for manifestation of digital malformations in mice. Female Slc:ICR mice were mated with F1 males (Os/+ or +/+) which were obtained from the cross between female ICR and C57BL-Os/+ mice. Pregnant females were treated with a single ip injection of 10, 7.5, 15 mg/kg of 5-fluorouracil on day 9, 10, 11 of gestation, respectively. The doses were subteratogenic or marginally teratogenic. Fetuses were examined externally and in double stained specimens for bone and cartilage. The incidence of axial oligodactyly in Os/+ fetuses was increased by 5-fluorouracil treatment on days 10 and 11. In the Os/+ fetuses treated with 5-fluorouracil, an increased incidence of postaxial oligodactyly was observed, those malformations not being induced by Os gene but by 5-fluorouracil treatment on day 11. The present experiment indicated that treatment with a teratogenic threshold dose of 5-fluorouracil increased the expressivity of Os gene on days 10 and 11.
[Imamura T et al; Teratology 40 (6): 656 (1989)]**PEER REVIEWED**

During evaluation of a potential in vitro (non-mammalian) screen for developmental toxicants, 5-fluorouracil, an antineoplastic agent and a known teratogen, was administered to developing Drosophila melanogaster (Oregon-R). This procedure involved exposure of Drosophila in culture vials throughout development (egg through third instar larvae) to 5-fluorouracil (0 to 2.0 ug/vial containing 1 g culture medium/5 ml water), with 2.0 ug/vial the estimated LC50. A mated untreated female was added to each culture vial and allowed to oviposit for 20 hr. Emerging adults, collected over 10 days, were examined microscopically (25X) for gross structural defects, and incidence data from flies exposed to 5-fluorouracil were compared to concurrent controls using chi-square. A unique defect, a "kidney" shaped eye, consisting of a severe indentation along the anterior eye margin, was seen in a number of treated flies. The incidence was concentration related, increasing from 0/175 in controls to 22/233 (9.4%) at the highest concentration (statistically significant, p< 0.001). This defect was not observed in over 15,000 control flies utilized in similar tests.
[Lynch DW et al; Toxicologist 10 (1): 125 (1990)]**PEER REVIEWED**

A study was undertaken to examine the issue of whether achieving a critical mass of cells and/or palatal shelf volume during vertical development of shelf is essential for reorientation to occur. In control and 5-fluorouracil treated hamster embryos' palatal shelves, at different times during gestation, the numbers of both epithelial and mesenchymal cells were counted and cross-sectional area was measured. DNA synthesis was measured by (3)H thymidine incorporation and was used as an index of growth by cell proliferation. The control data indicated that, unlike development during initial 24 hr, the later period of vertical palatal development was characterized by a steady level of mesenchymal and epithelial cell numbers and palatal shelf area. Following 5-fluorouracil treatment all the measurements were reduced, and until they reached the equivalent of control values, the palatal shelves did not reorient. The density of mesenchymal cells in the developing palate did not seem to affect cell number. On the basis of the analysis of results of the present study, along with those reported in the literature, it is suggested that, in hamsters, acquisition and maintenance of both a specified number of mesenchymal cells and shelf area, at least 24 hr prior to reorientation, may be critical for ensuing mesenchymal differentiation to enforce palatal shelf reorientation on schedule. 5-Fluorouracil affected these features to delay reorientation of the palatal shelf.
[Shah RM et al; Histol Histopathol 4 (4): 449-56 (1989)]**PEER REVIEWED**

The cytogenetic effects of 5-fluorouracil, 1-hexyl-carbamoyl-5-fluorouracil and 1-(2-tetrahydrofuryl)-5-fluorouracil were examined with the fetal liver micronucleus assay in mice. The frequencies of micronucleated polychromatic erythrocytes in fetal liver peaked at 27, 24 and 27 hr, respectively, after single ip injections into pregnant mice on day 13 of gestation. The highest frequency of micronucleated polychromatic erythrocytes by 5-fluorouracil treatment in fetal liver was 13.6%, whereas the frequency in maternal bone marrow was only 0.4%. The micronucleus frequency and the number of micronuclei per individual polychromatic erythrocyte were clearly dose dependent. These results suggest that the micronucleus test in fetal liver has particular advantages compared to maternal bone marrow for evaluating the cytogenetic effects of 5-fluorouracil and related cmpd after a single treatment. The cytogenetic effect was ranked 5-fluorouracil = 1-hexyl-carbamoyl-5-fluorouracil > 1-(2-tetrahydrofuryl)-5-fluorouracil, in both a time course study and a dose response study of micronucleus distribution.
[Nakamura M et al; Mutat Res 291 (1): 29-34 (1993)]**PEER REVIEWED**

A study was undertaken to examine the involvement of collagen synthesis during palate development in quail where mammalian type shelf reorientation is absent. Teratological observation showed that 100 ug 5-fluorouracil on day 4 of incubation increased the gap between the palatal shelves. Light microscopic observation indicated that the quail palatal shelves develop as horizontal ridges on day 5 and approximate on day 8 of incubation but never fuse. 5-fluorouracil treatment affected the approximation of palatal shelves. In separate experiments, both the control and 5-fluorouracil treated quail embryonic palates, which were dissected between days 5 and 10 of incubation, were incubated in a growth medium supplemented with (14)C proline. The rate of collagen synthesis, total protein, hydroxyproline levels, and collagen isotype were determined. The result showed that in control palates the rate of collagen synthesis increased fivefold between days 6 and 8 of incubation but dropped thereafter. In 5-fluorouracil exposed palates, the rate of collagen synthesis was lower than that in controls. It increased threefold between days 7 and 8 of incubation. HPLC measurement of hydroxyproline levels indicated that, in comparison to controls, hydroxyproline accumulation in 5-fluorouracil treated palates was reduced by 50% on day 6 and 75% on day 8 of incubation. Total protein content in 5-fluorouracil treated palate were also 50-70% lower than those in their control counterparts between days 5 and 10 of incubation. Gel electrophoresis showed that only type I collagen was synthesized in the developing palate of both the control and 5-fluorouracil treated quail embryo
[Benkhaial GS et al; J Craniofac Genet Dev Biol 13 (1): 6-17 (1993)]**PEER REVIEWED**

Non-Human Toxicity Values:

LD50 Rat oral 230 mg/kg
[Sax, N.I. Dangerous Properties of Industrial Materials Reports. New York: Van Nostrand Rheinhold, 1987.,p. V8 N6 64]**PEER REVIEWED**

LD50 Mouse oral 115 mg/kg
[Sax, N.I. Dangerous Properties of Industrial Materials Reports. New York: Van Nostrand Rheinhold, 1987.,p. V8 N6 64]**PEER REVIEWED**

LD50 Mouse iv 81 mg/kg
[Sax, N.I. Dangerous Properties of Industrial Materials Reports. New York: Van Nostrand Rheinhold, 1987.,p. V8 N6 64]**PEER REVIEWED**

Metabolism/Pharmacokinetics:

Metabolism/Metabolites:

... FLUOROURACIL ... IS CATABOLIZED IN MUCH SAME WAY AS IS URACIL. THUS, 5-FLUORO-5,6-DIHYDROURACIL IS FORMED ... IN MAN, IMPORTANT PRODUCT OF METABOLISM OF FLUOROURACIL IS UREA.
[Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. 1275]**PEER REVIEWED**

A small portion of fluorouracil is anabolized in the tissues to S-fluoro-2'-deoxyuridine and then to S-fluoro-2'-deoxyuridine-5'-monophosphate, the active metabolite of the drug. The major portion of the drug is degraded in the liver. The metabolites are excreted as respiratory carbon dioxide and as urea, alpha-fluoro-beta-alanine, alpha-fluoro-beta-guanidopropionic acid, and alpha-fluoro-beta-ureidopropionic acid in urine. Following a single iv dose of fluorouracil, approximately 15% of the dose is excreted in urine as intact drug within 6 hours; over 90% of this is excreted in the first hour.
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 574]**PEER REVIEWED**

Absorption, Distribution & Excretion:

GIVEN BY CONTINUOUS IV INFUSION FOR 24 HR, PLASMA CONCN IN RANGE OF 0.5-3.0 UMOLES ARE OBTAINED & URINARY EXCRETION OF FLUOROURACIL IS ONLY 4%.
[Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. 1229]**PEER REVIEWED**

FLUOROURACIL READILY ENTERS CEREBROSPINAL FLUID, & CONCN OF ABOUT 7 UMOLES ARE REACHED WITHIN 30 MIN AFTER IV ADMIN; VALUES ARE SUSTAINED FOR APPROX 3 HR & SUBSIDE SLOWLY DURING PERIOD OF 9 HR.
[Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. 1229]**PEER REVIEWED**

LIVER & MALIGNANT TUMORS STORE SOME OF 5-FLUOROURACIL.
[Thienes, C., and T.J. Haley. Clinical Toxicology. 5th ed. Philadelphia: Lea and Febiger, 1972. 229]**PEER REVIEWED**

FLUOROURACIL IS ADMINISTERED PARENTERALLY SINCE ABSORPTION AFTER INGESTION OF DRUGS IS UNPREDICTABLE & INCOMPLETE. METABOLIC DEGRADATION OCCURS, PARTICULARLY IN LIVER.
[Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. 1229]**PEER REVIEWED**

Fluorouracil crosses the placenta in rats. It is not known whether the drug is distributed into human milk.
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 574]**PEER REVIEWED**

Following iv administration of fluorouracil, no intact drug is detected in plasma after 3 hours.
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 574]**PEER REVIEWED**

Fluorouracil is distributed into tumors, intestinal mucosa, bone marrow, liver, and other tissues. Despite its limited lipid solubility, the drug readily crosses the blood-brain barrier and distributes into CSF and brain tissue. Distribution studies in humans and animals have usually shown a higher concentration of the drug or its metabolites in the tumor than in surrounding tissue or in corresponding normal tissue. It has also been shown that there is a longer persistence of fluorouracil in some tumors than in the normal tissues of the host, perhaps due to impaired uracil catabolism. From these data, it has been suggested that the drug may possibly have some specificity against certain tumors in comparison with normal tissues.
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 574]**PEER REVIEWED**

The purpose of this study was to determine the kinetics of 5-fluorouracil, a fluorinated pyrimidine with known nonlinear kinetics in a pregnant rat model and compare maternal and fetal disposition. A significant amt of 5-fluorouracil crosses the placenta and the relative fetal exposure increases in a dose dependent fashion. In the pregnant rat model, 5-fluorouracil exhibited nonlinear pharmacokinetics as reflected by an increasing half life, and a greater than proportional increase in the area under the concentration time curve with increasing dose. Fetal saturation of elimination occurred at a lower dose than in the maternal compartment.
[Boike GM et al; Gynecol Oncol 34 (2): 191-4 (1989)]**PEER REVIEWED**

Biological Half-Life:

RAPID IV ADMIN OF FLUOROURACIL PRODUCES PLASMA CONCN OF 0.1-1.0 MMOLES; PLASMA CLEARANCE IS RAPID (HALF-LIFE = 10-20 MIN). URINARY EXCRETION OF A SINGLE DOSE OF FLUOROURACIL GIVEN IV, AMT TO ONLY 11% IN 24 HR.
[Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. 1229]**PEER REVIEWED**

Following iv administration, the plasma elimination half-life averages about 16 minutes (range: 8-20 minutes) and is dose dependent.
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 574]**PEER REVIEWED**

Mechanism of Action:

FLUOROURACIL REQUIRES ENZYMATIC CONVERSION TO THE NUCLEOTIDE IN ORDER TO EXERT ITS CYTOTOXIC ACTIVITY. ... MAY BE CONVERTED TO FLUOROURIDINE BY URIDINE PHOSPHORYLASE & THEN TO F-UMP BY URIDINE KINASE, OR IT MAY REACT DIRECTLY WITH 5-PHOSPHORIBOSYL-1-PYROPHOSPHATE (PRPP), CATALYZED BY ... OROTATE PHOSPHORIBOSYL TRANSFERASE, TO FORM F-UMP.
[Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. 1228]**PEER REVIEWED**

... METHYL GROUP OF THYMINE IS INSERTED INTO 2'-DEOXYURIDINE-5'-PHOSPHATE BY SEQUENCE OF ENZYMATICALLY CATALYZED REACTIONS (THYMIMDYLATE SYNTHETASE SYSTEM) ... EFFECTS BIOSYNTHESES OF DNA. ... FLUOROURACIL ... HAVE PROVEN TO BE POTENT ANTIMETABOLITES THAT EXERT ... EFFECTS ... BY BLOCKING SYNTHESIS OF THYMIDYLIC ACIDS.
[Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. 1272]**PEER REVIEWED**

INHIBITORY NUCLEOTIDE IS NOT CAPABLE OF SERVING AS SUBSTRATE BUT BINDS TO ENZYME FROM 250 TO ABOUT 4000 TIMES MORE TIGHTLY THAN DOES DUMP. THIS UNUSUALLY POWERFUL INHIBITION OF KEY ENZYME IN SYNTH OF THYMIDYLATE IS SUFFICIENT TO EXPLAIN MOST OF CYTOTOXIC EFFECTS OF FLUOROURACIL & RELATED DERIV ... .
[Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. 1274]**PEER REVIEWED**

There have been notable advances in understanding of the interaction between F-dUMP and the enzyme thymidylate synthase, which is an important site of the cytotoxic action of the drug. The folate cofactor, N5-10-methylenetetrahydrofolate, and F-dUMP form a covalently bound ternary complex with the enzyme. This inhibitory complex resembles the transition state formed during the normal enzymatic reaction when dUMP is converted to thymidylate. Although the physiological complex progresses to the synthesis of thymidylate by transfer of the methylene group and two hydrogen atoms from folate to dUMP, this reaction is blocked in the inhibitory complex by the fluorine atom on F-dUMP; sustained inhibition of the enzyme results.
[Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. 1228]**PEER REVIEWED**

The precise mechanism (or mechanisms) of action of fluorouracil has not been determined, but the drug is thought to function as an antimetabolite in at least three different ways. The deoxyribonucleotide of the drug, 5-fluoro-2'-deoxyuridine-5'-phosphate, inhibits thymidylate synthetase thus inhibiting methylation of deoxyuridylic acid to thymidylic acid and thereby interfering with the synthesis of DNA. In addition, fluorouracil becomes incorporated to a small extent into RNA, producing a fraudulent RNA; thirdly, it inhibits utilization of preformed uracil in RNA synthesis by blocking uracil phosphatase.
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 574]**PEER REVIEWED**

The chemotherapeutic agent 5-fluorouracil is a known developmental toxicant in the rat both in vivo and in vitro. The mechanism of the drug's embryotoxic effect is unclear, but it has been postulated that 5-fluorouracil inhibits thymidylate synthase activity, leading to a deficiency of thymidine and a decrease in DNA synthesis. If this is the case, addition of excess exogenous thymidine should reverse the drug's embryotoxicity. Rat embryos were cultured beginning on day 10 of gestation (for 48 hr) in a whole embryo culture system. For the initial three hr of the culture period, 5-fluorouracil was present at a final concentration of 3 ug/ml. Following removal of 5-fluorouracil, various concentrations of thymidine were added for the remainder of the culture period. Treatment with 5-fluorouracil decreased the morphological score, number of somite pairs, crown-rump and head lengths, as well as DNA and protein contents; the incidence of malformations, particularly those affecting the tail, hindlimb bud, and brain, was increased. With addition of thymidine, there was attenuation of all parameters examined and fewer malformations. Exogenous thymidine was not able to reverse the effects of 5-fluorouracil completely, even if it was present for the entire 48 hr culture period, including the three hr 5-fluorouracil treatment phase. These results suggest that 5-fluorouracil may induce a thymidine deficiency in treated rat embryos, but some other effect(s) also appear to be involved in the embryotoxicity induced by the drug.
[Hansen DK, Grafton TF; In Vitro Toxicol 2 (4): 249-58 (1988)]**PEER REVIEWED**

Interactions:

PRETREATMENT OF MICE WITH TETRACYCLINE (PARTICULARLY), ACETYLSALICYLIC ACID, & SULFAMETHOXYPYRIDAZINE INCR LEVELS OF (14)C IN MOST TISSUES AFTER IP ADMIN OF (14)C 5-FLUOROURACIL TO MICE. THIS ANTIMETABOLITE APPEARED TO BE MORE TOXIC TO RATS WHEN CO-ADMIN WITH PRECEDING CMPD.
[The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A Review of the Literature Published Between 1970 and 1971. London: The Chemical Society, 1972. 119]**PEER REVIEWED**

... THYMIDINE ... INCR TOXICITY OF NUCLEOSIDE /FLUOROURACIL GIVEN AS SINGLE DAILY IV DOSES/. ... WHEN THYMIDINE IS GIVEN BY IV INFUSION, TOGETHER WITH FLOXURIDINE, EFFECTS ... CAN BE NULLIFIED ... .
[Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. 1275]**PEER REVIEWED**

To incr the complete response rate of patients with locally advanced head and neck cancer after 3 cycles of neoadjuvant chemotherapy, sequential methotrexate was added to the combination of cis-platin and continuous infusion fluorouracil. The feasibility of administering 3 additional cycles of the same regimen as adjuvant chemotherapy was examined. Thirty eight patients were treated; the median age was 53 yr and 36 patients had stage IV disease. Chemotherapy consisted of methotrexate 120 mg/sq m followed 24 hr later by cis-platin 100 mg/sq m and a 5 day continuous infusion of fluorouracil at 1000 mg/sq m/day. Of 34 patients evaluable for response to neoadjuvant chemotherapy, 9 had a complete response, 21 a partial response, 2 a minimal response, and 1 patient each stable disease and no response. Of 31 patients who received local therapy, 15 were treated with surgery and radiotherapy and 16 with radiotherapy alone. Of 25 patients eligible to receive adjuvant chemotherapy only 10 received all 3 intended cycles, while 15 received less or no adjuvant chemotherapy because of patient refusal, cumulative toxicity, or early disease progression. With a median follow up time of 39 mo, the median survival is estimated to be 20 mo. Of 8 patients with nasopharyngeal or paranasal sinus cancer, none had disease recurrence. Patients with good initial performance status and low N-stage also had a significant survival advantage. Chemotherapy-related toxicities consisted mainly of mucositis, requiring fluorouracil dose reduction in the majority of patients; similar toxicities were exacerbated in the adjuvant setting. The addition of methotrexate did not incr the complete response rate over what has been reported for the combination of cis-platin and fluorouracil alone.
[Vokes EE et al; J Clin Oncol 7 (7): 838-45 (1989)]**PEER REVIEWED**

Leukopenic and/or thrombocytopenic effects fluorouracil may be incr with concurrent or recent therapy with blood dyscrasia causing medications.
[US Pharmacopeial Convention; US Pharmacopeia Dispensing Information (USP DI); Drug Information for the Health Care Professional 12th ed, V.I p.1416 (1992)]**PEER REVIEWED**

Concurrent use /with leucovorin/ may incr the therapeutic and toxic effects of fluorouracil.
[US Pharmacopeial Convention; US Pharmacopeia Dispensing Information (USP DI); Drug Information for the Health Care Professional 12th ed, V.I p.1416 (1992)]**PEER REVIEWED**

Because normal defence mechanisms may be suppressed by fluorouracil therapy the patient's antibody responses to vaccine (killed virus) may be decr.
[US Pharmacopeial Convention; US Pharmacopeia Dispensing Information (USP DI); Drug Information for the Health Care Professional 12th ed, V.I p.1416 (1992)]**PEER REVIEWED**

Because normal defence mechanisms may be suppressed by fluorouracil therapy, concurrent use may potentiate the replication of the vaccine virus, may incr the side/adverse effects of the vaccine virus, and/or may decr the patient's antibody response to the vaccine.
[US Pharmacopeial Convention; US Pharmacopeia Dispensing Information (USP DI); Drug Information for the Health Care Professional 12th ed, V.I p.1416 (1992)]**PEER REVIEWED**

Embryotoxicity and teratogenicity of 5-fluorouracil and modulation of its effect by the depletors of glutathione were evaluated in mice. Pregnant ICR mice were ip injected with 25 mg/kg of 5-fluorouracil on day 11 of gestation (vaginal plug = day 0). Mice were pretreated ip with 250 mg/kg of phorone, a glutathione depleting agent and/or 200 mg/kg of buthionine sulfoximine (an inhibitor of glutathione biosynthesis) 4 hr before dosing with 5-fluorouracil. Dams were killed on day 17 of gestation. Fetuses were examined for external malformations, especially limb malformations. Pretreatment with phorone or buthionine sulfoximine decreased fetal wt and increased the frequency and severity of oligodactyly induced by 5-fluorouracil, as well as the reduction of maternal glutathione levels. Combined use of 125 mg/kg phorone and 100 mg/kg buthionine sulfoximine ip augmented growth retardation induced with 5-fluorouracil. Cotreatment with exogenous glutathione, at a dose of 300 mg/kg injected iv, could not suppress the augmentative effects of phorone and/or buthionine sulfoximine on 5-fluorouracil teratogenicity under these experimental conditions. These results indicate that the level of endogenous glutathione is one of the factors which significantly affects teratogenicity of 5-fluorouracil.
[Naya M et al; Teratology 41 (3): 275-80 (1990)]**PEER REVIEWED**

Embryotoxicity and teratogenicity of 5-fluorouracil and modulation of its effect by 1-2-oxothiazolidine-4-carboxylate, a cysteine pro-drug, were evaluated in mice. Pregnant ICR mice were ip injected with 25 mg/kg of 5-fluorouracil on day 11 of gestation (vaginal plug = day 0). Mice were pretreated ip with 950 mg/kg 1-2-oxothiazolidine-4-carboxylate 4 hr before dosing with 5-fluorouracil. Dams were killed on day 17 of gestation. Fetuses were examined for external malformations, especially limb malformations. Pretreatment with 1-2-oxothiazolidine-4-carboxylate decreased the frequency and severity of oligodactyly induced by 5-fluorouracil, although the differences were not significant statistically. There was little difference in liver glutathione levels, and body wt gain during gestation of dams between the 5-fluorouracil group and the 5-fluorouracil plus 1-2-oxothiazolidine-4-carboxylate group. Fetal mortality and fetal wt of the group treated with 5-fluorouracil alone were comparable with those of the group pretreated with 1-2-oxothiazolidine-4-carboxylate. In the present study, teratogenicity of 5-fluorouracil seemed to be slightly mitigated with 1-2-oxothiazolidine-4-carboxylate pretreatment.
[Naya M et al; Teratology 42 (6): 43A (1990)]**PEER REVIEWED**

In the observation of the toxic effect of 5-fluorouracil on pregnant rats and embryos, it was found that 5-fluorouracil became more toxic with the increasing drug doses. The results revealed that the body wt was decreased and the growth retarded in the pregnant rats and embryos and the rate of absorption of the embryos was increased. If 5-fluorouracil in combination with folic acid and vitamin C was fed to rats, its toxicity was increased, the rate of absorption of the embryos and the serum globulin in the pregnant rats were increased, and the rate of survival, the normal development of the embryos and the serum albumin and A/G ratios in the pregnant rats were significantly decreased. The results showed that 5-fluorouracil in combination with folic acid and vitamin C could significantly increase the toxic effect of 5-fluorouracil.
[Huangfu YM et al; Chung Kuo Yao Li Hsueh Yu Tu Li Hsueh Tsa Chih 5 (3): 214-6 (1991)]**PEER REVIEWED**

Pharmacology:

Therapeutic Uses:

Antimetabolites; Antimetabolites, Antineoplastic; Immunosuppressive Agents
[National Library of Medicine's Medical Subject Headings online file (MeSH, 1999)]**QC REVIEWED**

... USED TOPICALLY TO REMOVE MULTIPLE PREMALIGNANT ACTINIC KERATOSES. CURETTAGE OR CRYOTHERAPY IS PREFERRED FOR ISOLATED LESIONS. A 2% CONCENTRATION OFTEN IS ADEQUATE FOR KERATOSES ON FACE, FOREHEAD, BALD SCALP, & EARS. LESIONS ON HANDS & ARMS MAY REQUIRE HIGHER CONCN & LONGER TREATMENT.
[American Medical Association. AMA Drug Evaluations Annual 1991. Chicago, IL: American Medical Association, 1991. 1047]**PEER REVIEWED**

FLUOROURACIL IS WIDELY USED WITH VERY FAVORABLE RESULTS FOR TOPICAL TREATMENT OF PREMALIGNANT KERATOSES OF SKIN & MULTIPLE SUPERFICIAL BASAL-CELL CARCINOMAS.
[Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. 1230]**PEER REVIEWED**

PRODUCES PARTIAL RESPONSE IN 10 TO 30% OF PATIENTS WITH METASTATIC CARCINOMAS OF BREAST & GI TRACT; BENEFICIAL EFFECTS HAVE ALSO BEEN REPORTED IN HEPATOMA, AS WELL AS IN CARCINOMA OF OVARY, CERVIX, URINARY BLADDER, PROSTATE, PANCREAS, & OROPHARYNGEAL AREAS.
[Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. 1230]**PEER REVIEWED**

IT IS ANTINEOPLASTIC OF CHOICE IN TREATMENT OF CARCINOMA OF COLON OR RECTUM ... FLUOROURACIL MAY BE USEFUL IN TREATMENT OF NEOPLASMS OF STOMACH, GALL BLADDER ... & LIVER, &, TO LESSER EXTENT, THOSE OF UTERUS ... ESOPHAGUS, LARYNX, THYROID, PHARYNX ... .
[Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1079]**PEER REVIEWED**

... NEITHER /FLUOROURACIL & ITS DEOXYRIBONUCLEOSIDE/ ... IN DOSES TOLERATED BY NORMAL TISSUES, WILL CAUSE COMPLETE DISAPPEARANCE OF ANY NEOPLASM. HOWEVER, REMISSIONS FOR 5 YR & EVEN LONGER HAVE BEEN REPORTED, DESPITE PRESENCE OF RESIDUAL DISEASE. ... IN ... CASES WITH DISSEMINATED BREAST CANCER, INCR SURVIVAL HAS BEEN REPORTED.
[Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. 1276]**PEER REVIEWED**

FLUOROURACIL HAS BEEN ADMIN BY INFUSION INTO HEPATIC ARTERY WITH FAVORABLE RESULTS IN PATIENT WITH METASTASES TO LIVER.
[Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. 1276]**PEER REVIEWED**

AVG DURATION OF REMISSIONS INDUCED BY REPEATED COURSES OF THERAPY @ MONTHLY INTERVALS IS 5-6 MO, BUT RESPONSES LASTING 1-4 YR HAVE BEEN REPORTED.
[American Medical Association, AMA Department of Drugs, AMA Drug Evaluations. 3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977. 1119]**PEER REVIEWED**

USE OF SLOW IV INFUSIONS LASTING 2-8 HR MARKEDLY DECR TOXICITY ... . HOWEVER, RESULTS OF CLINICAL STUDIES HAVE INDICATED THAT RAPID INJECTIONS MAY BE MORE EFFECTIVE THAN SLOW INFUSIONS.
[American Medical Association, AMA Department of Drugs, AMA Drug Evaluations. 3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977. 1119]**PEER REVIEWED**

FLUOROURACIL IS CLASS II IMMUNOSUPPRESSIVE DRUG & HAS NOT BEEN USED IN ORGAN TRANSPLANTATION.
[Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1079]**PEER REVIEWED**

Antineoplastic agent indicated for iv use in the management of carcinoma of the colon, rectum, breast, stomach, and pancreas, and for the topical treatment of active or solar keratoses, and superficial basal cell carcenoma.
[Hussar, D.A. (ed.). Modell's Drugs in Current Use and New Drugs. 38th ed. New York, NY: Springer Publishing Co., 1992. 72]**PEER REVIEWED**

Fluorouracil is used for the palliative treatment of carcinoma of the colon, rectum, breast, stomach, and pancreas that is not amenable to surgery or irradiation. The drug also is used as an adjunct to surgery for the treatment of various solid tumors (eg, adenocarcinoma of the colon, rectal carcinoma, breast cancer).
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 574]**PEER REVIEWED**

Fluorouracil is less effective in the treatment of carcinomas of the ovary, cervix, urinary bladder, liver, and pancreas, although improvements in some patients have been reported. Carcinoma of the lung and malignant melanoma appear to be generally unresponsive to fluorouracil.
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 575]**PEER REVIEWED**

Drug Warnings:

Interactions:

Environmental Fate & Exposure:

Environmental Standards & Regulations:

CERCLA Reportable Quantities:

Releases of CERCLA hazardous substances are subject to the release reporting requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the requirements of 40 CFR part 355. Fluoroacil is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 500/10,000 lbs.
[40 CFR 355 (7/1/97)]**QC REVIEWED**

FDA Requirements:

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).
[21 CFR 200-299, 300-499, 820, and 860 (4/1/91]**PEER REVIEWED**

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl flourouracil, approved on the basis of safety and effectiveness by FDA under sections 505 and 507 of the Federal Food, Drug, and Cosmetic Act.
[DHHS/FDA; Approved Drug Products with Therapeutic Equivalence Evaluations 12th edition p.3-124 (1992)]**PEER REVIEWED**

Chemical/Physical Properties:

Molecular Formula:

C4-H3-F-N2-O2
[Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 654]**PEER REVIEWED**

Molecular Weight:

130.08
[Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 654]**PEER REVIEWED**

Color/Form:

WHITE TO PRACTICALLY WHITE CRYSTALLINE POWDER
[Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1079]**PEER REVIEWED**

CRYSTALS FROM WATER OR METHANOL-ETHER
[Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 654]**PEER REVIEWED**

Odor:

PRACTICALLY ODORLESS
[Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1079]**PEER REVIEWED**

Melting Point:

282 deg C (decomposes)
[Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 532]**PEER REVIEWED**

Solubilities:

1 G IN 80 ML WATER, 170 ML ALCOHOL & 55 ML METHANOL; PRACTICALLY INSOL IN CHLOROFORM, ETHER & BENZENE; SOLUBILITY IN AQ SOLN INCR WITH INCR PH OF SOLN
[Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1079]**PEER REVIEWED**

1 g/100 ml of propylene glycol
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 2251]**PEER REVIEWED**

Spectral Properties:

MAX ABSORPTION (0.1 N HYDROGEN CHLORIDE): 265-266 NM (E= 7070)
[Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 654]**PEER REVIEWED**

IR: 5062 (Coblentz Society Spectral Collection)
[Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 414]**PEER REVIEWED**

UV: 1400 (Absorption Spectra in the UV and visible Regions, Academic Press, New York)
[Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 414]**PEER REVIEWED**

NMR: 9:63C (Aldrich Library of Mass Spectra, Aldrich Chemical Co, Milwaukee, WI)
[Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 414]**PEER REVIEWED**

MASS: 4070 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63)
[Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 414]**PEER REVIEWED**

Other Chemical/Physical Properties:

DECOMPOSES AT 282-283 DEG C; SUBLIMES (0.1 MM): 190-200 DEG C
[Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 654]**PEER REVIEWED**

Chemical Safety & Handling:

Hazardous Decomposition:

When heated to decomposition it emits very toxic fumes of fluoride ion and oxides of nitrogen.
[Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 1450]**PEER REVIEWED**

Stability/Shelf Life:

STABLE WHEN EXPOSED TO AIR
[Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1079]**PEER REVIEWED**

Occupational Exposure Standards:

Manufacturing/Use Information:

Major Uses:

MEDICATION
**PEER REVIEWED**

Manufacturers:

PCR Inc, Hq, PO Box 1466, Gainsville, FL 32602 (904) 376-8246; Production site: Humacao, PR 00661
[SRI. 1992 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1992. 757]**PEER REVIEWED**

General Manufacturing Information:

COMMERCIAL PREPN ARE AVAILABLE I A VARIETY OF CONCN & VEHICLES. SOLN IN PROPYLENE GLYCOL ARE MORE ACTIVE THAN CREAM PREPN ... .
[American Medical Association. AMA Drug Evaluations Annual 1991. Chicago, IL: American Medical Association, 1991. 1048]**PEER REVIEWED**

SUSTAINED RELEASE OF LARGE NUMBERS OF STERILIZED MALES OF SPECIFIC INSECT SPECIES HAS YIELDED REMARKABLE CONTROL OF CERTAIN INSECT PESTS OF DOMESTIC ANIMALS & CROP PLANTS. ... STERILIZATION CAN BE EFFECTED ... CHEMICALLY, BY FEEDING COMPD OF KNOWN CHEMOSTERILANT ACTIVITY, SUCH AS ... FLUOROURACIL DERIV ... .
[White-Stevens, R. (ed.). Pesticides in the Environment: Volume 2. New York: Marcel Dekker, Inc., 1976. 295]**PEER REVIEWED**

Formulations/Preparations:

CREAM USP: 1 & 5%; INJECTION USP: 50 MG/ML. TOPICAL SOLN USP: 1, 2, & 5%.
[Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1079]**PEER REVIEWED**

Parenteral Injection, for iv use, 50 mg/ml, Adrucil, Adria; Fluorouracil Injection, Goldline, Lyphomed, Roche, Smith & Nepheq solopak; 50 mg/ml (2.5 g) pharmacy bulk package, Adrucil, Adria; Fluorouracil Injection, Lyphomed; 50 mg/ml (5 g) pharmacy bulk package, Fluorouracil Injection, Lyphomed, Smith & Nephew SoloPak.
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 577]**PEER REVIEWED**

Topical Cream, 1%, Fluoroplex (with benzyl alcohol), Herbert; 5%, Efudex (with parabens and propylene glycol), Roche Derm; Solution, 1%, Fluoroplex (with propylene glycol), Herbert; 2%, Efudex (with parabens and propylene glycol), Roche Derm; 5%, Efudex (with parabens and propylene glycol), Roche Derm.
[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). 2252]**PEER REVIEWED**

Ampules, 500 mg, Cream, 1% and 5%. Topical solution, 1%, 2%, and 5%.
[Hussar, D.A. (ed.). Modell's Drugs in Current Use and New Drugs. 38th ed. New York, NY: Springer Publishing Co., 1992. 72]**PEER REVIEWED**

Laboratory Methods:

Clinical Laboratory Methods:

GLC DETERMINATION OF FLUOROURACIL IN PLASMA @ CONCN AS LOW AS 0.1 UG/ML.
[FINCH ET AL; J PHARM SCI 67: 1489-90 (1978)]**PEER REVIEWED**

Matrix: Blood, bile, and urine. Analyte: Fluorouracil. Assay Procedure: Microbiological asssay. Limit of detection: 10 ng/ml. Matrix: Blood plasma. Analyte: Fluorouracil. Assay procedure: HPLC with UV detection. Limit of detection: 100 ng/ml. Sample Matrix: Blood serum. Analyte: Fluorouracil. Assay procedure: GC with ECD. Limit of detection 0.05 ng. /From table/
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer,1972-PRESENT. (Multivolume work).,p. V26 220 (1981)]**PEER REVIEWED**

Special References:

Synonyms and Identifiers:

Synonyms:

U-8953
**PEER REVIEWED**

Adrucil
**PEER REVIEWED**

Arumel
**PEER REVIEWED**

Cinco FU
**PEER REVIEWED**

2,4-DIOXO-5-FLUOROPYRIMIDINE
**PEER REVIEWED**

EFUDEX
**PEER REVIEWED**

Efudix
**PEER REVIEWED**

5-Faracil
**PEER REVIEWED**

5-Fluoracil (German)
**PEER REVIEWED**

FLUOROPLEX
**PEER REVIEWED**

5-fluoropyrimidin-2,4-diol
**PEER REVIEWED**

5-FLUOROPYRIMIDINE-2,4-DIONE
**PEER REVIEWED**

5-Fluoropyrimidine-2,4-(1H,3H)-dione
**PEER REVIEWED**

5-FLUOROURACIL
**PEER REVIEWED**

Fluoro-uracile
**PEER REVIEWED**

Fluoro-uracilo
**PEER REVIEWED**

Fluorouracilum
**PEER REVIEWED**

FLURACIL
**PEER REVIEWED**

Fluracilum
**PEER REVIEWED**

FLURIL
**PEER REVIEWED**

Fluroblastin
**PEER REVIEWED**

FLURO URACIL
**PEER REVIEWED**

FU
**PEER REVIEWED**

5-FU
**PEER REVIEWED**

NSC 19893
**PEER REVIEWED**

Phthoruracil
**PEER REVIEWED**

2,4(1H,3H)-PYRIMIDINEDIONE, 5-FLUORO-
**PEER REVIEWED**

RO 2-9757
**PEER REVIEWED**

Timazin
**PEER REVIEWED**

URACIL, 5-FLUORO-
**PEER REVIEWED**

Formulations/Preparations:

RTECS Number:

NIOSH/YR0350000

Administrative Information:

Hazardous Substances Databank Number: 3228

Last Revision Date: 20010809

Last Review Date: Reviewed by SRP on 9/9/1993

Update History:

Complete Update on 08/09/2001, 1 field added/edited/deleted.
Complete Update on 11/15/2000, 1 field added/edited/deleted.
Complete Update on 02/02/2000, 1 field added/edited/deleted.
Complete Update on 09/21/1999, 1 field added/edited/deleted.
Complete Update on 08/27/1999, 1 field added/edited/deleted.
Complete Update on 05/11/1999, 1 field added/edited/deleted.
Complete Update on 10/20/1998, 1 field added/edited/deleted.
Complete Update on 09/11/1998, 1 field added/edited/deleted.
Complete Update on 06/02/1998, 1 field added/edited/deleted.
Complete Update on 03/11/1998, 2 fields added/edited/deleted.
Field Update on 05/01/1997, 2 fields added/edited/deleted.
Complete Update on 05/11/1996, 1 field added/edited/deleted.
Complete Update on 01/26/1996, 1 field added/edited/deleted.
Complete Update on 03/29/1995, 1 field added/edited/deleted.
Complete Update on 12/30/1994, 1 field added/edited/deleted.
Complete Update on 04/26/1994, 32 fields added/edited/deleted.
Field Update on 03/25/1994, 1 field added/edited/deleted.
Complete Update on 02/05/1993, 1 field added/edited/deleted.
Field update on 12/29/1992, 1 field added/edited/deleted.
Complete Update on 01/28/1992, 1 field added/edited/deleted.
Complete Update on 01/07/1991, 8 fields added/edited/deleted.
Complete Update on 01/04/1985