Procarbazine hydrochloride

Procarbazine Hydrochloride is an alkylating agent, with anticancer activity.

Signaling Pathways >> Cell Cycle/DNA Damage >> DNA Alkylator/Crosslinker

Research Areas >> Cancer

Procarbazine Hydrochloride is an anticancer agent. Procarbazine is not cytotoxic to the LI 210 cells which lack cytochrome P-450 or monoamine oxidase activity[1].

Procarbazine Hydrochloride (50 mg/kg, i.p.) causes micronuclei in hematopoietic cells, but does not increase the lacZ mutant frequency (MF) in bone marrow of mice, similar to that in liver, testis, spleen, kidney, and lung. Procarbazine Hydrochloride (50 mg/kg, i.p.) has positive effect on lung, bone marrow, and spleen for carcinogenesis[2]. Procarbazine (450 mg/kg) significantly decreases testicular and epididymal weight and drastically reduces haploid cells and spermatogenic arrest in hamster[3].

Following Procarbazine or metabolite treatment, cells are diluted to 50.000/mL in 25-cm2 culture flasks (10 mL). Every 24 h, a 0.5-mL aliquot is removed, diluted 20-fold in Hematall isotonic diluent, and the cell number determined with a Coulter Model F electronic cell counter. Counts greater than 10,000/0.5 mL are corrected for coincidence. Cells are diluted in fresh culture media when cell density exceeded 1 × 106/mL. Cultures are maintained until the aggregate cell number approached 100 × 106/mL and doubling time has returned to 12 h. Cell survival is determined using Equation A, where TD(doubling time for cells of interest) is 12 h[1].

Mice[2] Male MutaTM Mouse animals (7-8 weeks old) are used after 2 weeks of acclimation. In the first experiment, 18 mice are injected intraperitoneally (i.p.) with 50 mg/kg Procarbazine hydrochloride in 10 mL saline/kg and eight mice are injected with 10 mL saline/kg as the vehicle control. Six treated mice are killed 7, 14, and 28 days after treatment, and four control mice are killed 7 and 28 days after the treatment. Killing is by cervical dislocation[2].

[1]. Erikson JM, et al. Cytotoxicity and DNA damage caused by the azoxy metabolites of procarbazine in L1210 tumor cells. Cancer Res. 1989 Jan 1;49(1):127-33.

[2]. Suzuki T, et al. Procarbazine genotoxicity in the MutaMouse; strong clastogenicity and organ-specific induction of lacZ mutations. Mutat Res. 1999 Aug 18;444(2):269-81.

[3]. Weissenberg R, et al. Procarbazine effects on spermatogenesis in golden hamster: a flow cytometric evaluation. Arch Androl. 2002 Mar-Apr;48(2):91-100.

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MOLECULAR FORMULA :

C12-H19-N3-O.Cl-H

MOLECULAR WEIGHT :

257.80

WISWESSER LINE NOTATION :

1Y1&MVR D1MM1 &GH

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

570 mg/kg

TOXIC EFFECTS :

Sense Organs and Special Senses (Eye) - lacrimation Behavioral - changes in motor activity (specific assay) Lungs, Thorax, or Respiration - dyspnea

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

490 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

350 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Unreported

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

785 mg/kg

TOXIC EFFECTS :

Blood - leukopenia Blood - thrombocytopenia Immunological Including Allergic - decreased immune response

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

560 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

699 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

710 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

540 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Unreported

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

1320 mg/kg

TOXIC EFFECTS :

Blood - leukopenia Blood - thrombocytopenia Immunological Including Allergic - decreased immune response

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Unreported

SPECIES OBSERVED :

Rodent - rabbit

DOSE/DURATION :

145 mg/kg

TOXIC EFFECTS :

Blood - leukopenia Blood - thrombocytopenia Immunological Including Allergic - decreased immune response

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

2700 mg/kg/5W-I

TOXIC EFFECTS :

Endocrine - changes in spleen weight Related to Chronic Data - death Related to Chronic Data - changes in ovarian weight

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

2100 mg/kg/5W-I

TOXIC EFFECTS :

Endocrine - changes in spleen weight Related to Chronic Data - death Related to Chronic Data - changes in ovarian weight

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

500 mg/kg

TOXIC EFFECTS :

Tumorigenic - equivocal tumorigenic agent by RTECS criteria Blood - tumors Skin and Appendages - tumors

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

1170 mg/kg/26W-I

TOXIC EFFECTS :

Tumorigenic - Carcinogenic by RTECS criteria Brain and Coverings - tumors Blood - lymphoma, including Hodgkin's disease

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

300 mg/kg

TOXIC EFFECTS :

Tumorigenic - Carcinogenic by RTECS criteria Lungs, Thorax, or Respiration - tumors Endocrine - tumors

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

125 mg/kg female 22 day(s) after conception

TOXIC EFFECTS :

Tumorigenic - equivocal tumorigenic agent by RTECS criteria Reproductive - Tumorigenic effects - transplacental tumorigenesis Brain and Coverings - tumors

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

2 gm/kg/8W-I

TOXIC EFFECTS :

Tumorigenic - Carcinogenic by RTECS criteria Lungs, Thorax, or Respiration - tumors Blood - leukemia

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

2340 mg/kg/42W-I

TOXIC EFFECTS :

Tumorigenic - Carcinogenic by RTECS criteria Brain and Coverings - tumors Blood - lymphoma, including Hodgkin's disease

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Primate - monkey

DOSE/DURATION :

4088 mg/kg/5Y-I

TOXIC EFFECTS :

Tumorigenic - equivocal tumorigenic agent by RTECS criteria Blood - leukemia

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Multiple routes

SPECIES OBSERVED :

Primate - monkey

DOSE/DURATION :

3270 mg/kg/69W-I

TOXIC EFFECTS :

Tumorigenic - equivocal tumorigenic agent by RTECS criteria Blood - leukemia Musculoskeletal - tumors

TYPE OF TEST :

TD - Toxic dose (other than lowest)

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

4680 mg/kg/26W-I

TOXIC EFFECTS :

Tumorigenic - Carcinogenic by RTECS criteria Blood - lymphoma, including Hodgkin's disease Skin and Appendages - tumors

TYPE OF TEST :

TD - Toxic dose (other than lowest)

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

1950 mg/kg/26W-I

TOXIC EFFECTS :

Tumorigenic - neoplastic by RTECS criteria Lungs, Thorax, or Respiration - tumors Blood - lymphoma, including Hodgkin's disease

TYPE OF TEST :

TD - Toxic dose (other than lowest)

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

500 mg/kg

TOXIC EFFECTS :

Tumorigenic - equivocal tumorigenic agent by RTECS criteria Blood - tumors Skin and Appendages - tumors

TYPE OF TEST :

TD - Toxic dose (other than lowest)

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

1136 mg/kg/8W-I

TOXIC EFFECTS :

Tumorigenic - neoplastic by RTECS criteria Lungs, Thorax, or Respiration - tumors Blood - leukemia

TYPE OF TEST :

TD - Toxic dose (other than lowest)

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

4680 mg/kg/52W-I

TOXIC EFFECTS :

Tumorigenic - Carcinogenic by RTECS criteria Brain and Coverings - tumors Blood - lymphoma, including Hodgkin's disease

TYPE OF TEST :

TD - Toxic dose (other than lowest)

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

2340 mg/kg/26W-I

TOXIC EFFECTS :

Tumorigenic - Carcinogenic by RTECS criteria Brain and Coverings - tumors Blood - lymphoma, including Hodgkin's disease

TYPE OF TEST :

TD - Toxic dose (other than lowest)

ROUTE OF EXPOSURE :

Multiple routes

SPECIES OBSERVED :

Primate - monkey

DOSE/DURATION :

20 gm/kg/8Y-I

TOXIC EFFECTS :

Tumorigenic - equivocal tumorigenic agent by RTECS criteria Blood - leukemia Musculoskeletal - tumors

TYPE OF TEST :

TD - Toxic dose (other than lowest)

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

1200 mg/kg/14W-C

TOXIC EFFECTS :

Tumorigenic - equivocal tumorigenic agent by RTECS criteria Lungs, Thorax, or Respiration - tumors Skin and Appendages - tumors

TYPE OF TEST :

TD - Toxic dose (other than lowest)

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

2560 mg/kg/8W-I

TOXIC EFFECTS :

Tumorigenic - neoplastic by RTECS criteria Lungs, Thorax, or Respiration - tumors Blood - leukemia

TYPE OF TEST :

TD - Toxic dose (other than lowest)

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

2 gm/kg/8W-I

TOXIC EFFECTS :

Tumorigenic - neoplastic by RTECS criteria Lungs, Thorax, or Respiration - tumors Blood - leukemia

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

120 mg/kg

SEX/DURATION :

female 9-14 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Embryo or Fetus - fetal death Reproductive - Specific Developmental Abnormalities - cardiovascular (circulatory) system

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

60 mg/kg

SEX/DURATION :

female 1-12 day(s) after conception

TOXIC EFFECTS :

Reproductive - Fertility - post-implantation mortality (e.g. dead and/or resorbed implants per total number of implants) Reproductive - Fertility - litter size (e.g. # fetuses per litter; measured before birth) Reproductive - Specific Developmental Abnormalities - eye/ear

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

120 mg/kg

SEX/DURATION :

female 1-12 day(s) after conception

TOXIC EFFECTS :

Reproductive - Fertility - abortion

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

4 mg/kg

SEX/DURATION :

female 13-16 day(s) after conception

TOXIC EFFECTS :

Reproductive - Specific Developmental Abnormalities - Central Nervous System

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

360 mg/kg

SEX/DURATION :

female 9-14 day(s) after conception

TOXIC EFFECTS :

Reproductive - Specific Developmental Abnormalities - body wall Reproductive - Specific Developmental Abnormalities - musculoskeletal system Reproductive - Specific Developmental Abnormalities - urogenital system

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

30 mg/kg

SEX/DURATION :

female 12-15 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Newborn - growth statistics (e.g.%, reduced weight gain)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

800 mg/kg

SEX/DURATION :

male 4 week(s) pre-mating

TOXIC EFFECTS :

Reproductive - Paternal Effects - testes, epididymis, sperm duct

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

2100 mg/kg

SEX/DURATION :

male 30 day(s) pre-mating

TOXIC EFFECTS :

Reproductive - Paternal Effects - testes, epididymis, sperm duct Reproductive - Paternal Effects - prostate, seminal vesicle, Cowper's gland, accessory glands

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

60 mg/kg

SEX/DURATION :

female 7-9 day(s) after conception

TOXIC EFFECTS :

Reproductive - Fertility - litter size (e.g. # fetuses per litter; measured before birth) Reproductive - Fertility - abortion Reproductive - Specific Developmental Abnormalities - Central Nervous System

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

60 mg/kg

SEX/DURATION :

female 7-9 day(s) after conception

TOXIC EFFECTS :

Reproductive - Specific Developmental Abnormalities - eye/ear Reproductive - Specific Developmental Abnormalities - craniofacial (including nose and tongue) Reproductive - Specific Developmental Abnormalities - musculoskeletal system

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

120 mg/kg

SEX/DURATION :

female 8-13 day(s) after conception

TOXIC EFFECTS :

Reproductive - Specific Developmental Abnormalities - cardiovascular (circulatory) system

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

360 mg/kg

SEX/DURATION :

female 8-13 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Embryo or Fetus - fetal death Reproductive - Specific Developmental Abnormalities - body wall Reproductive - Specific Developmental Abnormalities - urogenital system

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

2100 mg/kg

SEX/DURATION :

female 30 day(s) pre-mating

TOXIC EFFECTS :

Reproductive - Maternal Effects - ovaries, fallopian tubes Reproductive - Maternal Effects - uterus, cervix, vagina

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

200 mg/kg

SEX/DURATION :

male 1 day(s) pre-mating

TOXIC EFFECTS :

Reproductive - Fertility - pre-implantation mortality (e.g. reduction in number of implants per female; total number of implants per corpora lutea)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

100 mg/kg

SEX/DURATION :

male 1 day(s) pre-mating

TOXIC EFFECTS :

Reproductive - Effects on Embryo or Fetus - fetal death

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

400 mg/kg

SEX/DURATION :

male 1 day(s) pre-mating

TOXIC EFFECTS :

Reproductive - Paternal Effects - spermatogenesis (incl. genetic material, sperm morphology, motility, and count)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

200 mg/kg

SEX/DURATION :

female 14 day(s) after conception

TOXIC EFFECTS :

Reproductive - Specific Developmental Abnormalities - musculoskeletal system Reproductive - Specific Developmental Abnormalities - homeostasis

TYPE OF TEST :

Sex chromosome loss and nondisjunction

TYPE OF TEST :

DNA damage

TYPE OF TEST :

DNA inhibition

TYPE OF TEST :

Unscheduled DNA synthesis

TYPE OF TEST :

DNA inhibition

TYPE OF TEST :

Micronucleus test

TYPE OF TEST :

Micronucleus test

TYPE OF TEST :

Micronucleus test

TYPE OF TEST :

Specific locus test

TYPE OF TEST :

Specific locus test

TYPE OF TEST :

DNA damage

TYPE OF TEST :

Cytogenetic analysis

TYPE OF TEST :

Cytogenetic analysis

TYPE OF TEST :

Sister chromatid exchange

TYPE OF TEST :

Dominant lethal test

TYPE OF TEST :

Dominant lethal test

TYPE OF TEST :

Mutation in mammalian somatic cells

TYPE OF TEST :

Sperm Morphology

TYPE OF TEST :

Sister chromatid exchange

MUTATION DATA

TEST SYSTEM :

Mammal - pig

DOSE/DURATION :

168 mg/kg/4W (Continuous)

REFERENCE :

CRNGDP Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- Volume(issue)/page/year: 13,2153,1992 *** REVIEWS *** IARC Cancer Review:Animal Sufficient Evidence IMEMDT IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- Volume(issue)/page/year: 26,311,1981 IARC Cancer Review:Human Inadequate Evidence IMEMDT IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- Volume(issue)/page/year: 26,311,1981 IARC Cancer Review:Group 2A IMSUDL IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- Volume(issue)/page/year: 7,327,1987 *** NIOSH STANDARDS DEVELOPMENT AND SURVEILLANCE DATA *** NIOSH OCCUPATIONAL EXPOSURE SURVEY DATA : NOES - National Occupational Exposure Survey (1983) NOES Hazard Code - X4523 No. of Facilities: 32 (estimated) No. of Industries: 1 No. of Occupations: 2 No. of Employees: 1328 (estimated) No. of Female Employees: 289 (estimated)