FLUOROURACIL AND RELATED AGENTS

Editor's Note: This material is not listed in the Emergency Response Guidebook. Based on the material's physical and chemical properties, toxicity, or chemical group, a guide has been assigned. For additional technical information, contact one of the emergency response telephone numbers listed under Public Safety Measures.

DESIGNATIONS

NSC NUMBER:19893

MOLECULAR FORMULA

CAPECITABINE: C15H22FN3O6
FLUOROURACIL: C4H3FN2O2

ERG GUIDE NUMBER

151-SUBSTANCES - TOXIC (NON-COMBUSTIBLE)

SYNONYM REFERENCE

(RTECS , 1991; Budavari, 1989; EPA, 1985; Sax & Lewis, 1989; Sax & Lewis, 1987)

USES/FORMS/SOURCES

USES

FLUOROURACIL

IV: The intravenous formulation is indicated in the palliative management of carcinoma of the colon, rectum, breast, stomach, and pancreas in patients who are considered incurable by surgery or other means (Prod Info fluorouracil intravenous injection, 2014).
TOPICAL: Fluorouracil cream is approved for the treatment of actinic or solar keratosis lesions of the face, ears, and scalp (Prod Info TOLAK topical cream, 2015; Prod Info FLUOROPLEX(R) topical cream, 2004; Prod Info CARAC(TM) topical cream, 2003), as well as for the treatment of superficial basal carcinoma with the 5% strength (Prod Info Fluorouracil topical cream, 2010). The fluorouracil topical solution is used for the treatment of actinic and solar keratoses, as well as for the treatment of superficial basal cell carcinomas in patients with multiple lesions or at difficult treatment sites that could not be treated with other methods (Prod Info Fluorouracil topical solution, 2010).

CAPECITABINE

Capecitabine is a prodrug of fluorouracil used in the treatment of metastatic breast cancer that is refractory to paclitaxel and anthracycline-containing chemotherapy regimens and as adjuvant therapy in patients with Dukes' C colon cancer and metastatic colorectal cancer(Prod Info XELODA(R) oral tablets, 2015).

FLOXURIDINE

Floxuridine rapidly catabolizes to fluorouracil when given intra-arterially and is used for the palliative management of gastrointestinal adenocarcinoma that metastasized to the liver in patients who are considered incurable by surgery or other means (Prod Info floxuridine intra-arterial injection, 2008).

FORMS

FLUOROURACIL

IV: Available as 50 mg/mL in 10 mL or 20 mL vials for intravenous use (Prod Info fluorouracil intravenous injection, 2014)
TOPICAL: Available as a 0.5%, 1%, 4%, and 5% cream (Prod Info TOLAK topical cream, 2015; Prod Info Fluorouracil topical cream, 2010; Prod Info FLUOROPLEX(R) topical cream, 2004; Prod Info CARAC(TM) topical cream, 2003) and as a 2% and 5% topical solution (Prod Info Fluorouracil topical solution, 2010).

CAPECITABINE

Available as 150 mg and 500 mg tablets (Prod Info XELODA(R) oral tablets, 2015).

FLOXURIDINE

Available as a 500 mg powder for injection to be reconstituted with 5 mL of sterile water (Prod Info floxuridine intra-arterial injection, 2008).

-CLINICAL EFFECTS

GENERAL CLINICAL EFFECTS

USES: Fluorouracil (5-FU) is an antineoplastic used in the management of carcinoma of the esophagus, head and neck, colon, rectum, breast, stomach, and pancreas. Topical fluorouracil is used to treat actinic and solar keratoses. Capecitabine is a prodrug of fluorouracil, used in the treatment of colorectal cancer and metastatic breast cancer refractory to paclitaxel and anthracycline-containing chemotherapy as adjuvant therapy in patients with Dukes' C colon cancer and metastatic colorectal cancer. Floxuridine rapidly catabolizes to fluorouracil when given intra-arterially and is used for the management of gastrointestinal adenocarcinoma that metastasized to the liver.

PHARMACOLOGY: 5-Fluorouracil is a fluorinated pyrimidine antimetabolite which undergoes anabolic and catabolic reactions the same as uracil except it is converted to thymidine. 5-Fluorouracil, or fluorouracil, blocks the methylation reaction of deoxyuridylic acid to thymidylic acid and interferes with DNA synthesis and to a lesser extent inhibits the formation of RNA. This creates a thymine deficiency resulting in cell death, especially in cells which grow more rapidly and take up fluorouracil rapidly. Capecitabine is a prodrug and is extensively metabolized to 5-FU.

TOXICOLOGY: Fluorouracil effects rapidly dividing cells. In order to produce toxicity, fluorouracil must be metabolized into the compounds 5-fluorodeoxyurideine monophosphate and 5-fluorouracil triphosphate. Dihydropyrimidine dehydrogenase is an enzyme used in the initial and rate-limiting step of pyrimidine (and 5-FU) catabolism. In rare cases, an inherited deficiency of dipyrimidine dehydrogenase activity has led to severe toxicity (eg, stomatitis, diarrhea, neutropenia, and neurotoxicity) following therapeutic doses of 5-FU.

EPIDEMIOLOGY: Overdose of 5-FU is typically due to a medication error (ie, malfunction or incorrect programming of the intravenous pump) and is rare, but can be fatal, if it occurs.

WITH POISONING/EXPOSURE

OVERDOSE: Effects are expected to be an extension of adverse effects reported with therapeutic use and may include: severe nausea, vomiting, diarrhea, gastrointestinal ulceration and bleeding, and bone marrow depression (ie, thrombocytopenia, leukopenia, agranulocytosis, sepsis).

WITH THERAPEUTIC USE

ADVERSE EFFECTS: COMMON: Early symptoms include anorexia, stomatitis, esophagopharyngitis, diarrhea, nausea and vomiting. SEVERE: Major toxic effects result from myelosuppression. Clinical effects include palmar-plantar erythrodysesthesia, leukopenia, thrombocytopenia, and anemia.
LESS COMMON: Other potentially severe events: neurologic toxicity (ie, mental status changes, ataxia and neuropathy), cardiogenic shock, and gastrointestinal bleeding and perforation can develop. There have been infrequent reports of hepatotoxicity, ileitis, rhabdomyolysis, pulmonary edema, hypokalemia, and seizures.
CAPECITABINE: Dose-limiting toxicities with therapy can include gastrointestinal effects (ie, nausea, vomiting, diarrhea, abdominal pain), fatigue, dizziness, thrombocytopenia, and palmar-plantar erythrodysesthesia.

POTENTIAL HEALTH HAZARDS - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)

Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin.
Avoid any skin contact.
Effects of contact or inhalation may be delayed.
Fire may produce irritating, corrosive and/or toxic gases.
Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution.

ACUTE CLINICAL EFFECTS

SUMMARY

PHARMACOLOGY: 5-Fluorouracil is a fluorinated pyrimidine antimetabolite which undergoes anabolic and catabolic reactions the same as uracil except it is converted to thymidine. 5-Fluorouracil, or fluorouracil, blocks the methylation reaction of deoxyuridylic acid to thymidylic acid and interferes with DNA synthesis and to a lesser extent inhibits the formation of RNA. This creates a thymine deficiency resulting in cell death, especially in cells which grow more rapidly and take up fluorouracil rapidly. Capecitabine is a prodrug and is extensively metabolized to 5-FU.
TOXICOLOGY: Fluorouracil effects rapidly dividing cells. In order to produce toxicity, fluorouracil must be metabolized into the compounds 5-fluorodeoxyurideine monophosphate and 5-fluorouracil triphosphate. Dihydropyrimidine dehydrogenase is an enzyme used in the initial and rate-limiting step of pyrimidine (and 5-FU) catabolism. In rare cases, an inherited deficiency of dipyrimidine dehydrogenase activity has led to severe toxicity (eg, stomatitis, diarrhea, neutropenia, and neurotoxicity) following therapeutic doses of 5-FU.
EPIDEMIOLOGY: Overdose of 5-FU is typically due to a medication error (ie, malfunction or incorrect programming of the intravenous pump) and is rare, but can be fatal, if it occurs.
OVERDOSE: Effects are expected to be an extension of adverse effects reported with therapeutic use and may include: severe nausea, vomiting, diarrhea, gastrointestinal ulceration and bleeding, and bone marrow depression (ie, thrombocytopenia, leukopenia, agranulocytosis, sepsis).
ADVERSE EFFECTS: COMMON: Early symptoms include anorexia, stomatitis, esophagopharyngitis, diarrhea, nausea, and vomiting. SEVERE: Major toxic effects result from myelosuppression. Clinical effects include palmar-plantar erythrodysesthesia, leukopenia, thrombocytopenia, and anemia. LESS COMMON: Other potentially severe events: neurologic toxicity (ie, mental status changes, ataxia and neuropathy), cardiogenic shock, and gastrointestinal bleeding and perforation can develop. There have been infrequent reports of hepatotoxicity, ileitis, rhabdomyolysis, pulmonary edema, hypokalemia, and seizures. CAPECITABINE: Dose-limiting toxicities with therapy can include gastrointestinal effects (ie, nausea, vomiting, diarrhea, abdominal pain), fatigue, dizziness, thrombocytopenia, and palmar-plantar erythrodysesthesia.

Splash contact with fluorouracil may produce stinging or burning with blurred vision. No permanent ocular injury has been reported (Curran & Luce, 1989).

Cardiac arrest and infarction have been reported during infusion of fluorouracil (Millward et al, 1988; Soukop et al, 1978). Tachycardia and various ECG changes (ST elevation, inverted T waves, and tall, peaked T waves) have occurred during episodes of chest pain (Carpenter, 1972; Sanani et al, 1981). A case of acute reversible cardiogenic shock has been reported in a 48-year-old man with no history of heart disease (McKendall et al, 1989). Martin et al (1989) describe a case of fatal acute dilated cardiomyopathy associated with continuous infusion of fluorouracil.

The cardiotoxicity of 5-FU usually involves myocardial ischemia, arrhythmias, and congestive heart failure. Ischemic cardiopathy is the most common manifestation, with an incidence of 0.82% to 8% and a lethality rate of 12.5% to 28.5%. In one case heart failure was the initial sign, followed by ischemia upon resumption of 5-FU therapy (Lieutaud et al, 1996).

High doses of 5-FU can cause cardiogenic shock. In one case, the patient recovered with no ill effects (Akhtar et al, 1996).

Pulmonary edema without chest pain was a manifestation of reversible heart failure secondary to 5-fluorouracil (Chaudary et al, 1988).

Acute cerebellar syndrome is a form of neurotoxicity associated with use of 5-FU. Symptomatology may consist of somnolence, mental confusion, cerebellar ataxia, oculomotor disturbances, and slurred speech (Bixenman et al, 1977). Peripheral sensory neuropathy developed in addition to the acute cerebellar syndrome in one patient (Barbieux et al, 1996). Ischemic events and EEG changes have occurred with intra-arterial infusion of 5-FU (Larner et al, 1991). Neurotoxicity may develop in individuals with dihydropyrimidine dehydrogenase deficiency (Diasio et al, 1988).

Nausea, vomiting, and diarrhea are common with therapeutic doses (Smith et al, 1983). Stomatitis is often one of the dose-limiting adverse reactions of therapeutic 5-FU and may be a sign of severe impending bone marrow toxicity (Dorr & Fritz, 1980). GI ulceration or perforation with GI bleeding has been reported with therapeutic doses (Dorr & Fritz, 1980; Narsete et al, 1977). Paralytic ileus has been reported in serious overdoses (Dorr & Fritz, 1980).

Bone marrow depression is a delayed toxicity of 5-FU therapy. Peak effects may be noted from 7 to 14 days postexposure depending on cell type. Leukopenia, thrombocytopenia, and granulocytopenia may occur with therapeutic doses (Dorr & Fritz, 1980). Bone marrow depression is considered a dose-limiting toxicity. Acute immune hemolytic anemia and malignant hypercalcemia have been reported (Barnes & Harrah, 1974; Sandvei et al, 1987).

Alopecia and photosensitization from ultraviolet light have been reported (Dorr & Fritz, 1980; Umstead et al, 1991). Allergic contact dermatitis has been reported with the use of 5-fluorouracil ointment (Tennstedt & Lachapelle, 1987). Hyperpigmentation may occur on the face, hands, nail beds, and other body areas (Dorr & Fritz, 1980; Baran & Laugier, 1985).

Rapidly resolving skin irritation or skin discoloration requiring 2 weeks to resolve has been reported in 2 cases of accidental 5-FU contact with hands or fingers (Curran & Luce, 1989).

A case of an anaphylactic reaction with shock following a 10th dose of 5-fluorouracil intravenously was reported (DeBeer & Kabakow, 1979). A severe contact hypersensitivity reaction has been reported with a topical fluorouracil preparation (Sevadjian, 1985).

A dosage formulation of 5-FU in microspheres was less acutely toxic to mice than an equivalent aqueous solution (Hagiwara et al, 1996).

CHRONIC CLINICAL EFFECTS

Visual disturbance, reversible optic neuropathy, and ocular lesions consisting of bilateral conjunctival ulcers and ulcerative blepharitis have been reported with therapeutic doses (Dorr & Fritz, 1980; Adams et al, 1984; Insler & Helm, 1987). Extreme lacrimation may occur with therapeutic doses (Dorr & Fritz, 1980). Mucositis has also been reported (Meadows et al, 1991; Pazdur et al, 1991).

Severe chest pain and ischemia have been reported with therapeutic use of 5-FU (Underwood et al, 1983; Dent & McColl, 1975; Ensley et al, 1989; Freeman & Costanza, 1988). Hypotension has been associated with severe left ventricular dysfunction, a manifestation of cardiotoxicity (Jakubowski & Kemeny, 1988). Acute reversible cardiogenic shock, thromboembolism, fibrosing alveolitis, and infarct have been reported (Fielding et al, 1978; McKendall et al, 1989; Ensley et al, 1989; Gradishar et al, 1991).

Nausea, vomiting, and diarrhea are common with therapeutic doses (Smith et al, 1983). Stomatitis is often one of the dose-limiting adverse reactions of therapeutic 5-FU and may be a sign of severe impending bone marrow toxicity (Dorr & Fritz, 1980). GI ulceration or perforation with GI bleeding has been reported with therapeutic doses (Dorr & Fritz, 1980; Narsete et al, 1977).

A syndrome of ascites, hyperbilirubinemia, and hypoalbuminemia has been reported with fluorouracil and N-phosphonacetyl-L-aspartate therapy (Kemeny et al, 1991).

Bone marrow depression is a delayed toxicity of 5-FU therapy. Peak effects may be noted from 7 to 14 days post-exposure depending on cell type. Leukopenia, thrombocytopenia, and agranulocytopenia may occur with therapeutic doses (Dorr & Fritz, 1980). Bone marrow depression is considered a dose-limiting toxicity. Acute immune hemolytic anemia has been reported (Sandvei et al, 1987).

Alopecia has been reported as a delayed toxicity of therapeutic doses of 5-FU (Dorr & Fritz, 1980). Prodromal tingling progressing to tender, erythematous, swollen, desquamative eruptions of the palms and soles may occur but is limited to patients receiving prolonged infusions of high doses of fluorouracil (Feldman & Ajani, 1985). Bullous pemphigoid has been reported following topical therapy (Bart & Bean, 1970).

Rhabdomyolysis may occur following chronic topical exposure to 5-FU in propylene glycol based solution (Schmied & Levy, 1986).

Chronic vaginal ulcers have developed in women who were treated with topical 5-FU for papillomavirus-associated lesions (Krebs & Helmkamp, 1991).

-FIRST AID

FIRST AID AND PREHOSPITAL TREATMENT

Prehospital activated charcoal should be administered if possible after capecitabine overdose.

ACTIVATED CHARCOAL

PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

CHARCOAL DOSE

Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

ADVERSE EFFECTS/CONTRAINDICATIONS

Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

-MEDICAL TREATMENT

LIFE SUPPORT

Support respiratory and cardiovascular function.

SUMMARY

FIRST AID - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)

Move victim to fresh air.
Call 911 or emergency medical service.
Give artificial respiration if victim is not breathing.
Do not use mouth-to-mouth method if victim ingested or inhaled the substance;give artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device.
Administer oxygen if breathing is difficult.
Remove and isolate contaminated clothing and shoes.
In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes.
For minor skin contact, avoid spreading material on unaffected skin.
Keep victim warm and quiet.
Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed.
Ensure that medical personnel are aware of the material(s) involved and take precautions to protect themselves.

-RANGE OF TOXICITY

MINIMUM LETHAL EXPOSURE

CASE REPORTS

Death has been reported in a patient who received as little as 1000 mg of fluorouracil(Von Borstel et al, 2009).
In a review of 33 patients with inadvertent fluorouracil overdoses not treated with uridine triacetate, 29 patients died (Bamat, Tremmel, and O'Neil, 2010). Patients who died received doses ranging from 1000 mg to 27200 mg of fluorouracil. The 4 patients who recovered received doses ranging from 3588 mg to 7651 mg.
Severe toxicity and some deaths have been reported at 5-fluorouracil doses of 20 to 25 mg/kg (Dorr & Fritz, 1980).
CASE REPORT: A 55-year-old woman, with stage III sigmoid carcinoma, developed severe mucosal ulcerations, alopecia, palmar-plantar desquamation, and severe pancytopenia 9 days after receiving the first cycle of 5-fluorouracil and levofolinic acid combination chemotherapy, 425 mg/m(2) and 10 mg/m(2), respectively, given on days 1 to 5 of a 28-day cycle. She developed gram negative sepsis, multiorgan system failure, and died 15 days after the completion of the first cycle of chemotherapy. It was suspected that she may have had dihydropyrimidine dehydrogenase deficiency (Diaz et al, 2004).

MAXIMUM TOLERATED EXPOSURE

ROUTE OF EXPOSURE

INTRAVENOUS: 10 grams over 36 hours (Bamat, Tremmel, and O'Neil, 2010).
ORAL - 6 grams (Prod Info, 1980)
CONTINUOUS INTRAVENOUS INFUSION - 450 mg/m(2)/day (Spicer et al, 1988)

EFFICACY OF URIDINE TRIACETATE (ANTIDOTE)

Uridine triacetate appears to be an effective and lifesaving antidote. All patients treated to date with uridine triacetate following 5-FU overdose have recovered completely (more than 35 patients who received 5-FU doses ranging from 2,100 mg to 10,000 mg). Patients did not develop the anticipated gastrointestinal and hematologic toxicities following 5-FU overdose. Uridine triacetate was found to be effective after exposure to a range of doses of 5-FU; the highest dose for which a patient recovered was 10,000 mg of 5-FU infused over 3 hours. Two other patients recovered fully after receiving uridine triacetate following 5-FU doses of 8960 mg over 3 hours and 5000 mg over 17 minutes, respectively (Bamat, Tremmel, and O'Neil, 2010).
CASE REPORT: A 55-year-old, 77.9 kg man with colon cancer inadvertently received an overdose of 5-FU due to an infusion error and was treated with uridine triacetate about 18 hours after exposure. He was premedicated with ondansetron and received uridine triacetate 11 g every 6 hours orally for a total of 20 doses. He developed no clinical symptoms and his laboratory studies remained normal (McEvilly et al, 2011).

Carcinogenicity Ratings for CAS51-21-8 :

ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
EPA (U.S. Environmental Protection Agency, 2011): Not Listed
IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 3 ; Listed as: 5-Fluorouracil

3 : The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.

NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
MAK (DFG, 2002): Not Listed
NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

TOXICITY AND RISK ASSESSMENT VALUES

EPA IRIS

EPA Risk Assessment Values for CAS51-21-8 (U.S. Environmental Protection Agency, 2011):

Not Listed

TOXICITY VALUES

References: RTECS, 1990
- LD50- (ORAL)DOG:
- LD50- (INTRAVENOUS)GUINEA_PIG:
- LD50- (ORAL)RABBIT:
- LD50- (INTRACEREBRAL)RAT:
- LD50- (INTRAMUSCULAR)RAT:
- LD50- (INTRAPERITONEAL)RAT:
- LD50- (INTRAVENOUS)RAT:
- LD50- (ORAL)RAT:
- LD50- (RECTAL)RAT:
- LD50- (SUBCUTANEOUS)RAT:
- LDLo- (INTRATRACHEAL)MOUSE:
- LDLo- (INTRAVENOUS)RABBIT:
- TDLo- (INTRAVENOUS)HUMAN:
- TDLo- (ORAL)HUMAN:

-STANDARDS AND LABELS

WORKPLACE STANDARDS

ACGIH TLV Values for CAS51-21-8 (American Conference of Governmental Industrial Hygienists, 2010):

Not Listed

AIHA WEEL Values for CAS51-21-8 (AIHA, 2006):

Not Listed

NIOSH REL and IDLH Values for CAS51-21-8 (National Institute for Occupational Safety and Health, 2007):

Not Listed

OSHA PEL Values for CAS51-21-8 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

Not Listed

OSHA List of Highly Hazardous Chemicals, Toxics, and Reactives for CAS51-21-8 (U.S. Occupational Safety and Health Administration, 2010):

Not Listed

ENVIRONMENTAL STANDARDS

EPA CERCLA, Hazardous Substances and Reportable Quantities for CAS51-21-8 (U.S. Environmental Protection Agency, 2010):

Not Listed

EPA CERCLA, Hazardous Substances and Reportable Quantities, Radionuclides for CAS51-21-8 (U.S. Environmental Protection Agency, 2010):

Not Listed

EPA RCRA Hazardous Waste Number for CAS51-21-8 (U.S. Environmental Protection Agency, 2010b):

Not Listed
Editor's Note: The D, F, and K series waste numbers and Appendix VIII to Part 261 -- Hazardous Constituents were not included. Please refer to 40 CFR Part 261.

EPA SARA Title III, Extremely Hazardous Substance List for CAS51-21-8 (U.S. Environmental Protection Agency, 2010):

Listed as: Fluorouracil
Reportable Quantity, in pounds: 500

Only the statutory or final RQ is shown. For more information, see 40 CFR table 302.4.

Threshold Planning Quantity, in pounds:

500/10,000
Amount necessary to be covered by this standard. See 40 CFR 355.30.

Note(s): Not Listed

EPA SARA Title III, Community Right-to-Know for CAS51-21-8 (40 CFR 372.65, 2006; 40 CFR 372.28, 2006):

Listed as: Fluorouracil (5-Fluorouracil)
Effective Date for Reporting Under 40 CFR 372.30: 1/1/95
Lower Thresholds for Chemicals of Special Concern under 40 CFR 372.28:

DOT List of Marine Pollutants for CAS51-21-8 (49 CFR 172.101 - App. B, 2005):

Not Listed

EPA TSCA Inventory for CAS51-21-8 (EPA, 2005):

Listed as: 2,4(1H,3H)-Pyrimidinedione, 5-fluoro-

SHIPPING REGULATIONS

SURFACE

DOT -- Table of Hazardous Materials and Special Provisions (49 CFR 172.101, 2005):

Not Listed

ICAO International Shipping Name (ICAO, 2002):

Not Listed

LABELS

NFPA

NFPA Hazard Ratings for CAS51-21-8 (NFPA, 2002):

Not Listed

-HANDLING AND STORAGE

SUMMARY

INDUSTRIAL CHEMICALS

GLOVES: One study found latex gloves to be significantly less permeable to fluorouracil than PVC gloves (Stoikes et al, 1987).

-PERSONAL PROTECTION

SUMMARY

RECOMMENDED PROTECTIVE CLOTHING - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)

Wear positive pressure self-contained breathing apparatus (SCBA).
Wear chemical protective clothing that is specifically recommended by the manufacturer. It may provide little or no thermal protection.
Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations where direct contact with the substance is possible.

When administering fluorouracil, care should be taken to avoid inhalation of particles or exposure to skin (HSDB , 1990).

Latex gloves are significantly less permeable to fluorouracil in injectable form than PVC gloves; however, there is significant variability in the permeability of gloves from different lots. The intralot variability in permeation of these gloves may result in variable exposure of health care personnel during the administration of fluorouracil and other anticancer agents. Double gloving with either latex or PVC gloves and changing gloves every 30 minutes during the administration of fluorouracil is therefore recommended (Stoikes et al, 1987).

RESPIRATORY PROTECTION

Refer to "Recommendations for respirator selection" in the NIOSH Pocket Guide to Chemical Hazards on TOMES Plus(R) for respirator information.

Self-contained (positive pressure) breathing apparatus is recommended for fire fighting and handling spills (EPA, 1985).

PROTECTIVE CLOTHING

CHEMICAL PROTECTIVE CLOTHING. Search results for CAS 51-21-8.

Specific recommendations and test data for this chemical were not found in the available manufacturers' product literature. A complete list of consulted manufacturers and references is presented below.

-PHYSICAL HAZARDS

FIRE HAZARD

SUMMARY

Editor's Note: This material is not listed in the Emergency Response Guidebook. Based on the material's physical and chemical properties, toxicity, or chemical group, a guide has been assigned. For additional technical information, contact one of the emergency response telephone numbers listed under Public Safety Measures.
POTENTIAL FIRE OR EXPLOSION HAZARDS - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)
- Non-combustible, substance itself does not burn but may decompose upon heating to produce corrosive and/or toxic fumes.
- Containers may explode when heated.
- Runoff may pollute waterways.
No specific fire fighting procedures have been recommended for this agent (EPA, 1985).

FLAMMABILITY CLASSIFICATION

NFPA Flammability Rating for CAS51-21-8 (NFPA, 2002):

Not Listed

FIRE CONTROL/EXTINGUISHING AGENTS

SMALL FIRE PRECAUTIONS - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)

Dry chemical, CO2 or water spray.

LARGE FIRE PRECAUTIONS - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)

Water spray, fog or regular foam.
Move containers from fire area if you can do it without risk.
Dike fire control water for later disposal; do not scatter the material.
Use water spray or fog; do not use straight streams.

TANK OR CAR/TRAILER LOAD FIRE PRECAUTIONS - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)

Fight fire from maximum distance or use unmanned hose holders or monitor nozzles.
Do not get water inside containers.
Cool containers with flooding quantities of water until well after fire is out.
Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank.
ALWAYS stay away from tanks engulfed in fire.
For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn.

NFPA Extinguishing Methods for CAS51-21-8 (NFPA, 2002):

Not Listed

COMBUSTION TOXICITY

When heated to decomposition, fluorouracil emits very toxic fumes of fluoride and nitrogen oxide (Sax & Lewis, 1989).

DUST/VAPOR HAZARD

When heated to decomposition, fluorouracil emits very toxic fumes of fluoride and nitrogen oxide (Sax & Lewis, 1989).

REACTIVITY HAZARD

Fluorouracil is stable when exposed to air (HSDB , 1990).

EVACUATION PROCEDURES

SUMMARY

Editor's Note: This material is not listed in the Table of Initial Isolation and Protective Action Distances.

SPILL - PUBLIC SAFETY EVACUATION DISTANCES - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)

Increase, in the downwind direction, as necessary, the isolation distance of at least 25 to 50 meters (80 to 160 feet) in all directions.

FIRE - PUBLIC SAFETY EVACUATION DISTANCES - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)

If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions.

PUBLIC SAFETY MEASURES - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)

CALL Emergency Response Telephone Number on Shipping Paper first. If Shipping Paper not available or no answer, refer to appropriate telephone number:

MEXICO:

SETIQ:

01-800-00-214-00 in the Mexican Republic;
For calls originating in Mexico City and the Metropolitan Area: 5559-1588;
For calls originating elsewhere, call: 011-52-555-559-1588.

CENACOM:

01-800-00-413-00 in the Mexican Republic;
For calls originating in Mexico City and the Metropolitan Area: 5550-1496, 5550-1552, 5550-1485, or 5550-4885;
For calls originating elsewhere, call: 011-52-555-550-1496, or 011-52-555-550-1552; 011-52-555-550-1485, or 011-52-555-550-4885.

ARGENTINA:

CIQUIME:

0-800-222-2933 in the Republic of Argentina;
For calls originating elsewhere, call: +54-11-4613-1100.

BRAZIL:

PRÓ-QUÍMICA:

0-800-118270 (Toll-free in Brazil);
For calls originating elsewhere, call: +55-11-232-1144 (Collect calls are accepted).

COLUMBIA:

CISPROQUIM:

01-800-091-6012 in Colombia;
For calls originating in Bogotá, Colombia, call: 288-6012;
For calls originating elsewhere, call: 011-57-1-288-6012.

CANADA:

CANUTEC:

613-996-6666 (Collect calls are accepted);
*666 cellular (in Canada only).

UNITED STATES:

CHEMTREC®:

1-800-424-9300 (Toll-free in the U.S., Canada, and the U.S. Virgin Islands);
703-527-3887 for calls originating elsewhere (Collect calls are accepted).

CHEM-TEL, INC.:

1-800-255-3924 (Toll-free in the U.S., Canada, and the U.S. Virgin Islands);
813-248-0585 for calls originating elsewhere (Collect calls are accepted).

INFOTRAC:

1-800-535-5053 (Toll-free in the U.S., Canada, and the U.S. Virgin Islands);
352-323-3500 for calls originating elsewhere (Collect calls are accepted).

3E COMPANY:

1-800-451-8346 (Toll-free in the U.S., Canada, and the U.S. Virgin Islands);
760-602-8703 for calls originating elsewhere (Collect calls are accepted).

NATIONAL RESPONSE CENTER (NRC):

1-800-424-8802 - (24 hours) (Toll-free in the U.S., Canada, and the U.S. Virgin Islands);
202-267-2675 for calls in the District of Columbia.

MILITARY SHIPMENTS:

703-697-0218 - Explosives/ammunition incidents (Collect calls are accepted);
1-800-851-8061 - All other dangerous goods incidents.

NATIONWIDE POISON CONTROL CENTER (United States only):

1-800-222-1222 (Toll-free in the U.S.).

For additional details see the section entitled "WHO TO CALL FOR ASSISTANCE" under the ERG Instructions.
As an immediate precautionary measure, isolate spill or leak area in all directions for at least 50 meters (150 feet) for liquids and at least 25 meters (75 feet) for solids.
Keep unauthorized personnel away.
Stay upwind.
Keep out of low areas.

AIHA ERPG Values for CAS51-21-8 (AIHA, 2006):

Not Listed

DOE TEEL Values for CAS51-21-8 (U.S. Department of Energy, Office of Emergency Management, 2010):

Listed as Fluorouracil
TEEL-0 (units = mg/m3): 0.75
TEEL-1 (units = mg/m3): 2.5
TEEL-2 (units = mg/m3): 19
TEEL-3 (units = mg/m3): 100
Definitions:

TEEL-0: The threshold concentration below which most people will experience no adverse health effects.
TEEL-1: The airborne concentration (expressed as ppm [parts per million] or mg/m(3) [milligrams per cubic meter]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory effects. However, these effects are not disabling and are transient and reversible upon cessation of exposure.
TEEL-2: The airborne concentration (expressed as ppm or mg/m(3)) of a substance above which it is predicted that the general population, including susceptible individuals, could experience irreversible or other serious, long-lasting, adverse health effects or an impaired ability to escape.
TEEL-3: The airborne concentration (expressed as ppm or mg/m(3)) of a substance above which it is predicted that the general population, including susceptible individuals, could experience life-threatening adverse health effects or death.

AEGL Values for CAS51-21-8 (National Research Council, 2010; National Research Council, 2009; National Research Council, 2008; National Research Council, 2007; NRC, 2001; NRC, 2002; NRC, 2003; NRC, 2004; NRC, 2004; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; United States Environmental Protection Agency Office of Pollution Prevention and Toxics, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2009; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2008; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2007; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2005; National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, 2006; 62 FR 58840, 1997; 65 FR 14186, 2000; 65 FR 39264, 2000; 65 FR 77866, 2000; 66 FR 21940, 2001; 67 FR 7164, 2002; 68 FR 42710, 2003; 69 FR 54144, 2004):

Not Listed

NIOSH IDLH Values for CAS51-21-8 (National Institute for Occupational Safety and Health, 2007):

Not Listed

CONTAINMENT/WASTE TREATMENT OPTIONS

SUMMARY

SPILL OR LEAK PRECAUTIONS - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)
- Do not touch damaged containers or spilled material unless wearing appropriate protective clothing.
- Stop leak if you can do it without risk.
- Prevent entry into waterways, sewers, basements or confined areas.
- Cover with plastic sheet to prevent spreading.
- Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers.
- DO NOT GET WATER INSIDE CONTAINERS.
RECOMMENDED PROTECTIVE CLOTHING - EMERGENCY RESPONSE GUIDEBOOK, GUIDE 151 (ERG, 2004)
- Wear positive pressure self-contained breathing apparatus (SCBA).
- Wear chemical protective clothing that is specifically recommended by the manufacturer. It may provide little or no thermal protection.
- Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations where direct contact with the substance is possible.
No specific disposal guidelines have been recommended for this agent. The following information is general recommendations for non-specific medicines (EPA, 1985).

SMALL LEAK/SPILL

Take up with sand or other noncombustible absorbent material and place into containers for later disposal (EPA, 1985).
Small dry spills: Place material into a clean, dry container, using a clean shovel, and cover. Move container from spill area (EPA, 1985).

LARGE LEAK/SPILL

Keep unnecessary people away; isolate the hazard area and deny entry. Stay upwind; keep out of low areas. Wear self-contained (positive pressure) breathing apparatus and full protective clothing (EPA, 1985).
Dike far ahead of liquid spill for later disposal (EPA, 1985).

-ENVIRONMENTAL HAZARD MANAGEMENT

POLLUTION HAZARD

There was no information on pollution hazards for fluorouracil in available references at the time of this review.

ENVIRONMENTAL FATE AND KINETICS

OTHER

OTHER
- There was no information on environmental kinetics for fluorouracil in available references at the time of this review.

ENVIRONMENTAL TOXICITY

There was no information on environmental toxicity for fluorouracil in available references at the time of this review.

-PHYSICAL/CHEMICAL PROPERTIES

MOLECULAR WEIGHT

CAPECITABINE:

359.35 (Prod Info XELODA(R) oral tablets, 2015)

FLUOROURACIL:

130.08 (Prod Info Fluorouracil IV injection, 2008; Prod Info EFUDEX(R) topical cream, topical solution, 2005)

DESCRIPTION/PHYSICAL STATE

CAPECITABINE is a white to off-white crystalline powder with an aqueous solubility of 26 mg/mL at 20 degrees C (Prod Info XELODA(R) oral tablets, 2015).

FLUOROURACIL is a white or nearly white, odorless, crystalline powder that is sparingly soluble in water and slightly soluble in alcohol. One gram is soluble in 100 mL of propylene glycol (Prod Info EFUDEX(R) topical cream, topical solution, 2005; Prod Info Fluorouracil IV injection, 2008; Sax & Lewis, 1987); crystals from water or methanol-ether (Budavari, 1996).

FLUOROURACIL: The injection solution may discolor slightly during storage, but potency and safety are not adversely affected (Prod Info Fluorouracil IV injection, 2008).

FLUOROURACIL: If a precipitate occurs in the injection solution due to exposure to low temperatures, resolubilize the solution by heating it to 140 degrees F and shaking it vigorously. Allow the solution to cool to body temperature before using (Prod Info Fluorouracil IV injection, 2008).

FLUOROURACIL: Injection: approximately 9.2 (Prod Info Fluorouracil IV injection, 2008); topical cream: approximately 8.5 (Prod Info FLUOROPLEX(R) topical cream, 2004)

FREEZING/MELTING POINT

MELTING POINT

Sublimes (190 to 200 degrees C and 0.1 mmHg) (Budavari, 1989)

SOLUBILITY

IN WATER

1 g/80 mL (HSDB , 1990)
Soluble in water or methanol-water mixtures (Sax & Lewis, 1987).
Solubility in aqueous solutions increases with increasing pH of the solution (HSDB , 1990).

IN ORGANIC SOLVENTS

1 g/170 mL of alcohol (HSDB , 1990)
1 g/55 mL of methanol (HSDB , 1990)
Practically insoluble in chloroform, ether, and benzene (HSDB , 1990).
Soluble in water or methanol-water mixtures (Sax & Lewis, 1987).

SPECTRAL CONSTANTS

UV max (0.1 N HCl): 265 to 266 nanometers (Budavari, 1989)

OTHER/PHYSICAL

DISSOCIATION CONSTANT

pKa, 8, 13 (Baselt & Cravey, 1989)

-REFERENCES

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65 FR 14186: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.

65 FR 39264: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.

65 FR 77866: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.

66 FR 21940: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2001.

67 FR 7164: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2002.

68 FR 42710: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2003.

69 FR 54144: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2004.

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Information to evaluate chemical incidents

Information to evaluate chemical incidents