Carcinogenicity

Chlorambucil is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans.

Properties

Chlorambucil is a nitrogen mustard that acts as a bifunctional alkylating agent and is used as a pharmaceutical agent (IARC 1987). It exists at room temperature as an off-white granular powder with a slight odor. It is soluble in ethanol, chloroform, ethyl acetate, benzene, and ether, and readily soluble in acid or alkaline solutions. In water, the free acid is insoluble, but the sodium salt is soluble. Chlorambucil is sensitive to oxidation and moisture (IARC 1981). Physical and chemical properties of chlorambucil are listed in Table 1.

Table 1

Properties of Chlorambucil.

Use

Chlorambucil is used primarily as an antineoplastic agent to treat cancer of the blood and lymphatic system, such as Hodgkin and non-Hodgkin lymphoma, chronic lymphocytic leukemia, and primary (Waldenström) macroglobulinemia. It is also used as a chemotherapeutic agent for Kaposi sarcoma and cancer of the breast, lung, cervix, ovary, and testis. Chlorambucil is an immunosuppressive agent that has been used to treat rheumatoid arthritis, systemic lupus erythematosus, acute and chronic glomerulonephritis, nephrotic syndrome, psoriasis, Wegener granulomatosis, chronic active hepatitis, and cold agglutinin disease (IARC 1981). It is also used in veterinary medicine to treat cancer and immune-mediated diseases, including lymphocytic leukemia, multiple myeloma, ovarian cancer, lymphoma, polycythemia rubra vera, pemphigus diseases, eosinophilic granuloma complex, inflammatory bowel disease, feline infectious peritonitis, immune-mediated hemolytic anemia, and immune-mediated platelet destruction (Brooks 2009).

Production

All of the chlorambucil used in the United States is imported from the United Kingdom (HSDB 2009). However, the drug has been formulated in the United States since 1957. Annual U.S. sales of chlorambucil in the mid 1970s were estimated at less than 20 kg (44 lb) (IARC 1975). In 2009, chlorambucil was available from six U.S. suppliers (ChemSources 2009), and one product approved by the U.S. Food and Drug Administration contained chlorambucil as the active ingredient (FDA 2009). Annual U.S. imports of chlorambucil were 32 to 34 kg (71 to 75 lb) in the early 1970s, increasing slightly to 48 kg (106 lb) in 1978 (HSDB 2009; IARC 1981).

Exposure

The primary routes of potential human exposure to chlorambucil are ingestion, inhalation, and dermal contact. Continuous and intermittent oral-treatment schedules are employed for patients treated with chlorambucil. Chlorambucil is available in 2-mg tablets. The initial daily dose is 0.1 to 0.2 mg/kg of body weight (for a total daily dose of 4 to 10 mg) for 3 to 6 weeks. If clinical improvement or bone-marrow toxicity occurs, the dose is reduced. A daily maintenance dose of 2 mg may be required (FDA 2009; IARC 1981). Occupational exposure to chlorambucil may occur through dermal contact or inhalation of dust during formulation, packaging, and administration of the drug product. The National Occupational Exposure Survey (conducted from 1981 to 1983) estimated that 3,719 workers, including 2,018 women, potentially were exposed to chlorambucil (NIOSH 1990). No more recent estimates of exposure were found.

Regulations

Guidelines

References

1. Brooks WC. 2009. Chlorambucil (Leukeran®). The Pet Pharmacy. Veterinary Information Network; http://www​.veterinarypartner​.com/Content​.plx?P=A&S=0&C​=0&A=1328
2. ChemIDplus. 2009. ChemIDplus Advanced. National Library of Medicine; Last accessed: 10/26/09. http://chem​.sis.nlm.nih​.gov/chemidplus/chemidheavy.jsp and select Registry Number and search on CAS number.
3. ChemSources. 2009. Chem Sources - Chemical Search. Chemical Sources International; Last accessed: 10/26/09. http://www​.chemsources​.com/chemonline.html and search on chlorambucil.
4. FDA. 2009. The Electronic Orange Book. U.S. Food and Drug Administration; Last accessed: 10/26/09. https://www​.fda.gov/cder/ob/default.htm and select Search by Active Ingredient and search on chlorambucil.
5. HSDB. 2009. Hazardous Substances Data Bank. National Library of Medicine; Last accessed: 10/26/09. http://toxnet​.nlm.nih​.gov/cgi-bin/sis/htmlgen?HSDB and search on CAS number.
6. IARC. 1975. Chlorambucil. In Some Aziridines, N-, S-, and O-Mustards and Selenium. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans, vol. 9. Lyon, France: International Agency for Research on Cancer. pp. 125–134.
7. IARC. 1981. Chlorambucil. In Some Antineoplastic and Immunosuppressive Agents. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, vol. 26. Lyon, France: International Agency for Research on Cancer. pp. 115–136. [PubMed: 6944253]
8. IARC. 1987. Chlorambucil. In Overall Evaluations of Carcinogenicity. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, suppl. 7. Lyon, France: International Agency for Research on Cancer. pp. 144–145.
9. NIOSH. 1990. National Occupational Exposure Survey (1981-83). National Institute for Occupational Safety and Health; https://www​.cdc.gov/noes/noes1/x3995sic​.html