Fluorouracil
CAS No. 51-21-8
 
 

Return to Fluorouracil Adverse Effects

ACTIVITY: Former Insect Chemosterilant; now used as a chemotherapeutic drug

Systematic Name: 2,4(1H,3H)-Pyrimidinedione, 5-fluoro-

Structure:

Adverse Effects:

Anemia
Ataxia
Blood
Bone
Brain
Developmental Toxicant
Embryotoxic
Endocrine: Gonadotoxicity / Spermatogenesis

Endocrine: Ovary
Endocrine:
Thymus
Gastrointestinal tract
Genotoxic
Heart
Lung
Teratogen
Urinary Tract

Regulatory Information
(only comprehensive for the US)
US EPA Registered: No 
Other Information
Molecular Formula: C4-H3-F-N2-O2 
Manufacturers: Syngenta (Novartis)
Systematic Names: 2,4(1H,3H)-Pyrimidinedione, 5-fluoro-
5-Fluorouracil
Fluorouracil
Uracil, 5-fluoro-  
Of special interest:
TOXNET profile from Hazardous Substances Data Bank
Identified by the State of California as "Known to Cause Developmental Toxicity" - Prop 65 
Included on The List of Extremely Hazardous Substances US 40 CFR - CHAPTER I - PART 355 - updated October 3, 2003
Extremely Hazardous Substance. US EPA Chemical Profile. November 30, 1987 

Rationale for US EPA to add Fluorouracil to the Toxic Release Inventory

A major use of fluorouracil is in the palliative treatment of carcinoma of the colon, rectum, breast, stomach, and pancreas that is not amenable to surgery or irradiation. The major toxic effects of fluorouracil are on the normal, rapidly proliferating tissues particularly of the bone marrow and lining of the gastrointestinal tract. Leukopenia, predominantly of the granulocytopenic type, thrombocytopenia, and anemia occur commonly with intravenous fluorouracil therapy at doses ranging from 6 to 12 mg/kg. Pancytopenia and agranulocytosis also have occurred.

Developmental abnormalities or other effects on newborns were reported in offspring of women receiving 150 or 240 mg/kg fluorouracil intravenously during weeks 11 to 14 or 20 to 31 of pregnancy. In addition, maternal toxicity to the reproductive organs, toxicity to the fetus, and developmental abnormalities have been reported in mice, rats, and hamsters receiving oral, intraperitoneal, or intramuscular doses of fluorouracil ranging from 10 to 700 mg/kg.

Chronic neurotoxic effects were noted in dogs fed fluorouracil at a dietary dose of 2 mg/kg/day for 6 months. In this study, animals were examined at the end of 3 months and 6 months. At the end of the experiment, or at death, the brain was removed and examined (only one dog survived the entire 6-month period). Histological sections of the brain showed the presence large multiple monolocular vacuoles in the wall of the fornix of the third ventricle.

EPA believes that there is sufficient evidence for listing fluorouracil on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the toxicity of this substance to bone marrow, and on the developmental and chronic neurotoxicity data for this chemical.

USEPA/OPPT. Support Document for the Health and Ecological Toxicity Review of TRI Expansion Chemicals. U. S. Environmental Protection Agency, Washington, DC (1993). As cited by US EPA in: Federal Register: January 12, 1994. Part IV. 40 CFR Part 372. Addition of Certain Chemicals; Toxic Chemical Release Reporting; Community Right-to-Know; Proposed Rule.


Chemical Sterilants, Virus Vectors, Insect Control
Author: M.L. SHARMA
Acta Hort. (ISHS) 94:403-406, 1981

Abstract:
Several chemosterilants have been tested in the laboratory and chemicals as 5-fluorouracil, thiotepa, tepa, metepa and apholate have given excellent results in the reduction of reproductive capacity as well as in sterility of Tetranychus urticae, Aphis fabae, Acyrthosiphon pisum, Myzus persicae and Macrosiphum euphorbiae. Because of their perennial nature, the fruit trees provide excellent testing material and as such the above mentioned chemosterilants may be tested in experimental orchards against Aphis pommi, Myzus persicae and Tetranychus species that abound these perennials. Since the sterility by 5-fluorouracil and thiotepa seems to be prolonged upto F2 generation, these products may have a long range effect in the aphid control. Since M. persicae and A. pommi are virus vectors, not only we can expect an eradication of the virus vector but also an attenuation of the viruses itself because of the nature of chemosterilants used. In the use of thiotepa (maximum of 0.5%) the stability of the chemosterilant can be prolonged when used in solutions with sodium bicarbonate. These applications will probably bring a solution to virus vector eradication as well as to viruses propagation. At this stage, however, no guarantee seems available against the destruction of useful insects as Coccinellidae and Chrysopidae. The above suggestions should be considered as experimentation hypothesis under controlled and isolated orchards. In all cases great care must be taken in the application of chemosterilants because of the sterility and side effects they may cause to the animal and human life.


TOXNET profile from Hazardous Substances
Data Bank
"readily crosses the blood-brain barrier and distributes into CSF and brain tissue."
"Potential Adverse Effects on Fetus: Exposure in first trimester: skeletal abnormalities; hypoplasia of aorta, lungs, thymus, and gastrointestinal tract; and urinary tract abnormalities. Fetus exposed in third trimester had cyanosis and clonus."
"the incidence of malformations, particularly those affecting the tail, hindlimb bud, and brain, was increased."
inhibits "DNA, RNA, and protein synthesis"

PDR entry for EFUDEX (ICN) fluorouracil) TOPICAL SOLUTIONS AND CREAM Ref: Physicians Desk Reference (On-line 2001) [Efudex® is made by by Hoffmann-La Roche Inc.]

"Fluorouracil produced petite mutations in Saccharomyces cerevisiae and was positive in the mironucleus test (bone marrow cells of male mice)."
"There is evidence that the metabolism of fluorouracil in the anabolic pathway blocks the methylation reaction of deoxyuridylic acid to thymidylic acid. In this manner fluorouracil interferes with the synthesis of deoxyribonucleic acid (DNA) and to a lesser extent inhibits the formation of ribonucleic acid (RNA). Since DNA and RNA are essential for cell division and growth, the effect of fluorouracil may be to create a thymine deficiency which provokes unbalanced growth and death of the cell. The effects of DNA and RNA deprivation are most marked on those cells which grow more rapidly and take up fluorouracil at a more rapid rate."
"cases of miscarriage and a birth defect (ventricular septal defect) have been reported when Efudex was applied to mucous membrane areas during pregnancy. "
 
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