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Toxicity Effects

CAS Registry Number: 66-75-1

Selected toxicity information from HSDB, one of the National Library of Medicine's databases. 2.

Names 1

    Human Toxicity Excerpts

    • Dermatologic reactions including pruritus, dermatitis, some degree of alopecia, and hyperpigmentation have been reported in patients receiving the drug. Neurologic symptoms including irritability, nervousness, mental cloudiness, or mental depression have also occurred. Dermatologic and neurologic effects have not been definitely attributed to uracil mustard in all cases, however. Rarely, hepatotoxicity manifested by jaundice and glycogen infiltration has been reported. As a result of extensive purine catabolism accompanying rapid cellular destruction, hyperuricemia may occur in some patients receiving uracil mustard, especially those with non-Hodgkin's lymphomas or leukemia. In some patients, uric acid nephropathy progressing to acute renal failure may result. These effects may be minimized by adequate hydration, alkalinization of the urine, and/or administration of allopurinol.[McEvoy G.K. (ed.). American Hospital Formulary Service-Drug Information 96. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1996 (Plus Supplements)., p. 795] **PEER REVIEWED**
    • GI toxicity occurs frequently and is manifested by anorexia, epigastric distress, abdominal pain, nausea, vomiting, and diarrhea. In some patients, adverse GI effects have been severe enough to necessitate discontinuance of the drug. Oral ulceration has been reported as a toxic reaction to uracil mustard.[McEvoy G.K. (ed.). American Hospital Formulary Service-Drug Information 96. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1996 (Plus Supplements)., p. 795] **PEER REVIEWED**
    • Gonadal suppression, resulting in amenorrhea or azoospermia, may occur in patients taking antineoplastic therapy, especially with the alkylating agents. In general, these effects appear to be related to dose and length of therapy and may be irreversible. Prediction of the degree of testicular or ovarian function impairment is complicated by the common use of combinations of several antineoplastics, which makes it difficult to assess the effects of individual agents. /Antineoplastic agents/[USP Convention. USPDI - Drug Information for the Health Care Professional. 16th ed. Volume I. Rockville, MD: U.S. Pharmaceutical Convention, Inc. 1996 (Plus updates)., p. 2939] **PEER REVIEWED**
    • Secondary malignancies are potential delayed effects of many antineoplastic agents, although it is not clear whether the effect is related to their mutagenic or immunosuppressive action. The effect of dose and duration of therapy is also unknown, although risk seems to increase with long-term use. Although information is limited, available data seem to indicate that the carcinogenic risk is greatest with the alkylating agents. /Antineoplastic agents/[USP Convention. USPDI - Drug Information for the Health Care Professional. 16th ed. Volume I. Rockville, MD: U.S. Pharmaceutical Convention, Inc. 1996 (Plus updates)., p. 2939] **PEER REVIEWED**
    • The Carcinogen Assessment Group in EPA's Research and Development Office has evaluated uracil mustard for carcinogenicity. According to their analysis, the weight of evidence for uracil mustard is group B2, which is based on no evidence in humans and sufficient evidence in animals. As a group B2 chemical, uracil mustard is considered a possible human carcinogen.[USEPA; Methodology for Evaluating Potential Carcinogenicity in Support of Reportable Quantity Adjustments Pursuant to Cercla Section 102 (Draft) p.A-56 (1986) OHEA-C-073] **PEER REVIEWED**
    • The major adverse effect uracil mustard is hematologic toxicity. Leukopenia and thrombocytopenia occur frequently at therapeutic dosage, and anemia has also been reported. Depression of platelet counts appears to be more pronounced and to occur more frequently than depression of leukocyte counts. Although the manufacturer states that most patients have recovered from toxic reactions to uracil mustard within 2-3 weeks after discontinuance of the drug, hematopoietic toxicity of uracil mustard is cumulative and, as the total dose hematopoietic toxicity of uracil mustard is cumulative and, as the total dose approaches 1 mg/kg, irreversible damage to the bone marrow may occur.[McEvoy G.K. (ed.). American Hospital Formulary Service-Drug Information 96. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1996 (Plus Supplements)., p. 795] **PEER REVIEWED**
    • Transformation to acute leukemia is known to occur in polycythemia vera and essential thrombocythemia. The alkylating agent, uracil mustard, which is an effective agent for controlling thrombocytosis, has not been reported to be leukemogenic. We have treated 29 patients, with uracil mustard (9 treated continuously and 20 treated intermittently): with polycythemia vera, 16 with essential thrombocythemia, & 2 with myelofibrosis. Three patients developed acute leukemia, two after continuous therapy. These two patients with polycythemia vera had received the fourth highest and highest total dose of uracil mustard, and their duration of treatment was the third and fourth longest among the nine patients treated continuously, respectively. One out of 20 patients treated intermittently with uracil mustard developed acute leukemia. This patient with essential thrombocythemia had received the highest total dose of uracil mustard, and her duration of treatment was the longest among the 20 patients treated intermittently.[Toh BT et al; Am J Hematol 28 (1): 58-60 (1988)] **PEER REVIEWED** PubMed Abstract

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    Non-Human Toxicity Excerpts

    • 3 GROUPS OF 20 A/HE MICE OF BOTH SEXES, 6-8 WK OLD, RECEIVED IP INJECTIONS OF URACIL MUSTARD IN TRICAPRYLIN OVER 24-WK PERIOD (TOTAL DOSES, 40, 20 & 8 MG/KG PER BODY WT). AT THE END OF THIS PERIOD THERE WERE 15, 18 & 19 SURVIVORS, RESPECTIVELY, & ALL DEVELOPED LUNG ADENOMAS & ADENOCARCINOMAS, AVG BEING 23, 12 & 3.7 TUMORS/MOUSE, RESPECTIVELY.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V9 237 (1975)] **PEER REVIEWED**
    • ADMIN OF URACIL MUSTARD TO FEMALE RATS IN DOSES OF 0.3 & 0.6 MG/KG BODY WT ON THE 12TH DAY OF PREGNANCY PRODUCED MALFORMATIONS IN SURVIVING OFFSPRING @ 21 DAYS: EXENCEPHALY, RETARDED & CLUBBED APPENDAGES, & DEFORMED PAWS & TAIL WERE SEEN.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V9 239 (1975)] **PEER REVIEWED**
    • GROUPS OF 25 MALE & 25 FEMALE SWISS MICE, 6 WK OLD, WERE GIVEN IP INJECTIONS OF 0.12 OR 0.5 MG/KG BODY WT THRICE WEEKLY FOR 6 MO, FOLLOWED BY OBSERVATION FOR A FURTHER 12 MONTHS, AT WHICH TIME THE ANIMALS WERE KILLED. LUNG TUMORS OCCURRED IN 7/37 MALES AND IN 23/40 FEMALES. LIVER TUMORS OCCURRED 4/37 MALES AND OVARIAN TUMORS AND LYMPHOMAS OCCURRED IN 10/40 AND 20/40 FEMALES, RESPECTIVELY. THE INCIDENCES OF EACH TUMOR TYPE WERE SIGNIFICANTLY GREATER IN TREATED ANIMALS THAN IN CONTROLS.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V9 238 (1975)] **PEER REVIEWED**
    • HIGHER DOSES OF URACIL MUSTARD CAUSED HEPATIC CHANGES CONSISTING OF EARLY PORTAL CIRRHOSIS.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V9 239 (1975)] **PEER REVIEWED**
    • MALE & FEMALE A/J MICE, 4-6 WK OLD WERE GIVEN IP INJECTIONS OF URACIL MUSTARD IN TRICAPRYLIN OR IN 1% ACACIA SOLN THRICE WEEKLY FOR 4 WK (TOTAL DOSES RANGED FROM 0.18-12 MG/KG PER BODY WT). THIRTY NINE WEEKS AFTER THE FIRST INJECTION, THE SURVIVORS WERE KILLED AND EXAMINED FOR LUNG ADENOMAS & ADENOCARCINOMAS. /THE RESULTS WERE/: DOSE 0.76 MG/KG BODY WT: SURVIVORS 54/60; % MICE WITH TUMORS 85%; MEAN NUMBER OF TUMORS/MOUSE 2.0; DOSE 3.00 MG/KG BODY WT: SURVIVORS 52/60; % MICE WITH TUMORS 100%; MEAN NUMBER OF TUMORS/MOUSE 6.6; DOSE 12.0 MG/KG BODY WT: SURVIVORS 28/60; % MICE WITH TUMORS 100%; MEAN NUMBER OF TUMORS/MOUSE 15.6; DOSE 0.18 MG/KG BODY WT: SURVIVORS 55/60; % MICE WITH TUMORS 56%; MEAN NUMBER OF TUMORS/MOUSE 0.9.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V9 237 (1975)] **PEER REVIEWED**
    • TWO GROUPS OF 25 MALE AND 25 FEMALE CHARLES RIVER CD RATS, 6 WEEKS OLD, WERE GIVEN THRICE WEEKLY IP INJECTIONS OF 0.15 OR 0.3 MG/KG BODY WEIGHT FOR 6 MONTHS, FOLLOWED BY OBSERVATION FOR A FURTHER 12 MONTHS, AT WHICH TIME THE ANIMALS WERE KILLED. PERITONEAL SARCOMAS OCCURRED IN 10/38 MALES AND 8/39 FEMALES (P< 0.001); LYMPHOMAS OCCURED IN 6/38 MALES (P< 0.001) AND IN 4/39 FEMALES (P= 0.004); PANCREATIC TUMORS WERE FOUND IN 3/38 MALES (P< 0.005); OVARIAN TUMORS AND MAMMARY CARCINOMAS WERE FOUND IN 4/39 (P< 0.001) AND 8/39 (P=0.03) FEMALES, RESPECTIVELY. THE INCIDENCES OF EACH TUMOR TYPE WERE SIGNIFICANTLY GREATER IN TREATED ANIMALS THAN IN CONTROLS.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V9 238 (1975)] **PEER REVIEWED**
    • URACIL MUSTARD INDUCED EXTENSIVE DAMAGE IN RAT BONE MARROW & TESTIS.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V9 239 (1975)] **PEER REVIEWED**

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    Human Toxicity Values

    • None found

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    Non-Human Toxicity Values

    • None found

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    Absorption, Distribution And Excretion

    • 2-(14)C-URACIL MUSTARD WAS ADMIN @ DOSE OF 4 MG TO 265 WALKER CARCINOSARCOMA BEARING HOLZMAN RATS. INCORPORATION OF (14)C LABEL INTO MACROMOLECULES IN SUBCELLULAR FRACTIONS OF VARIOUS TISSUES WAS MEASURED FOR 6 HR AFTER ADMIN AND WAS GENERALLY FOUND TO BE MAXIMAL BY 1 HR & TO BE MORE EXTENSIVE IN RNA THAN IN DNA OR PROTEIN.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V9 239 (1975)] **PEER REVIEWED**
    • THE REACTION OF 0.2 UMOLES/ML URACIL MUSTARD WITH HEPARINIZED HUMAN BLOOD @ 37 DEG C IN VITRO WAS MEASURED COLORIMETRICALLY: ABOUT 50% OR ORIGINAL DRUG WAS NO LONGER DETECTABLE AFTER 30 MIN.[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V9 239 (1975)] **PEER REVIEWED**
    • URACIL MUSTARD IS ABSORBED QUICKLY BUT NOT COMPLETELY AFTER ORAL ADMIN IN DOGS. CONCN IN PLASMA DECLINED AFTER EITHER ORAL (2 MG/KG) OR IV (1 MG/KG) ADMIN, & NO EVIDENCE OF DRUG WAS DETECTED @ 2 HR. LESS THAN 1% OF ADMIN DOSE WAS RECOVERED UNCHANGED IN URINE.[Gilman, A.G., L.S.Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 7th ed. New York: Macmillan Publishing Co., Inc., 1985., p. 1258] **PEER REVIEWED**

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    Metabolism/Metabolites

    • None found

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    Tsca Test Submissions

    • None found

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    Footnotes

    1 Source: the NTP's CEBS database.

    2 Source: the National Library of Medicine's Hazardous Substance Database, 02/28/2017.

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