*** CHEMICAL IDENTIFICATION ***
RTECS NUMBER : HP1750000
CHEMICAL NAME : 5H-Dibenzo(b,e)(1,4)diazepine,
8-chloro-11-(4-methyl-1-piperazinyl)-
CAS REGISTRY NUMBER : 5786-21-0
BEILSTEIN REFERENCE NO. : 0764984
REFERENCE : 5-25-11-00364 (Beilstein Handbook Reference)
LAST UPDATED : 199807
DATA ITEMS CITED : 33
MOLECULAR FORMULA : C18-H19-Cl-N4
MOLECULAR WEIGHT : 326.86
WISWESSER LINE NOTATION : T C676 BM INJ FG J- AT6N DNTJ D1
COMPOUND DESCRIPTOR : Drug
Mutagen
Reproductive Effector
Human
SYNONYMS/TRADE NAMES :
* 8-Chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo(b,e)(1,4)diazepine
* Clozapin
* Clozapine
* HF-1854
* Iprox
* Leponex
* W-801
*** HEALTH HAZARD DATA ***
** ACUTE TOXICITY DATA **
TYPE OF TEST : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE : Oral
SPECIES OBSERVED : Human - man
DOSE/DURATION : 3280 mg/kg/82W-I
TOXIC EFFECTS :
Blood - agranulocytosis
REFERENCE :
AJPSAO American Journal of Psychiatry. (American Psychiatric Assoc.,
Circulation Dept., 1400 K St., NW, Washington, DC 20005) V.78- 1921-
Volume(issue)/page/year: 153,1503,1996
TYPE OF TEST : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE : Oral
SPECIES OBSERVED : Human - child
DOSE/DURATION : 4762 ug/kg
TOXIC EFFECTS :
Behavioral - ataxia
Behavioral - muscle contraction or spasticity
Behavioral - antipsychotic
REFERENCE :
AJEMEN American Journal of Emergency Medicine. (WB Saunders, Philadelphia,
PA) V.1- 1983- Volume(issue)/page/year: 14,462,1996
TYPE OF TEST : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE : Oral
SPECIES OBSERVED : Human - man
DOSE/DURATION : 5357 ug/kg/5D-I
TOXIC EFFECTS :
Behavioral - hallucinations, distorted perceptions
Behavioral - antipsychotic
Cardiac - pulse rate increase, without fall in BP
REFERENCE :
JCPYDR Journal of Clinical Pyschopharmacology. (Williams & Wilkins Co., 428
E. Preston St., Baltimore, MD 21202) V.1- 1981- Volume(issue)/page/year:
12,139,1992
TYPE OF TEST : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE : Oral
SPECIES OBSERVED : Human - man
DOSE/DURATION : 429 mg/kg/60D-I
TOXIC EFFECTS :
Behavioral - muscle contraction or spasticity
REFERENCE :
AJPSAO American Journal of Psychiatry. (American Psychiatric Assoc.,
Circulation Dept., 1400 K St., NW, Washington, DC 20005) V.78- 1921-
Volume(issue)/page/year: 152,649,1995
TYPE OF TEST : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE : Oral
SPECIES OBSERVED : Human - woman
DOSE/DURATION : 20 mg/kg
TOXIC EFFECTS :
Behavioral - coma
Gastrointestinal - changes in structure or function of endocrine pancreas
Blood - leukopenia
REFERENCE :
AIMEAS Annals of Internal Medicine. (American College of Physicians, 4200
Pine St., Philadelphia, PA 19104) V.1- 1927- Volume(issue)/page/year:
121,722,1994
TYPE OF TEST : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE : Oral
SPECIES OBSERVED : Human - woman
DOSE/DURATION : 280 mg/kg/5W-I
TOXIC EFFECTS :
Liver - hepatitis (hepatocellular necrosis), diffuse
Blood - eosinophilia
REFERENCE :
AJPSAO American Journal of Psychiatry. (American Psychiatric Assoc.,
Circulation Dept., 1400 K St., NW, Washington, DC 20005) V.78- 1921-
Volume(issue)/page/year: 150,985,1993
TYPE OF TEST : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE : Oral
SPECIES OBSERVED : Human - man
DOSE/DURATION : 27 mg/kg/13D-I
TOXIC EFFECTS :
Autonomic Nervous System - smooth muscle relaxant (mechanism undefined,
spasmolytic)
Behavioral - hallucinations, distorted perceptions
Behavioral - ataxia
REFERENCE :
JCLPDE Journal of Clinical Psychiatry. (Physicians Postgraduate Press,
Inc., POB 240008, Memphis, TN 38124) V.39- 1978-
Volume(issue)/page/year: 55,38,1994
TYPE OF TEST : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE : Oral
SPECIES OBSERVED : Human
DOSE/DURATION : 5 mg/kg/7D-I
TOXIC EFFECTS :
Cardiac - pulse rate increase, without fall in BP
REFERENCE :
ARZNAD Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag,
Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951-
Volume(issue)/page/year: 22,919,1972
TYPE OF TEST : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE : Oral
SPECIES OBSERVED : Human - man
DOSE/DURATION : 4286 ug/kg/11D-I
TOXIC EFFECTS :
Gastrointestinal - hypermotility, diarrhea
Blood - changes in cell count (unspecified)
Nutritional and Gross Metabolic - body temperature increase
REFERENCE :
JCPYDR Journal of Clinical Pyschopharmacology. (Williams & Wilkins Co., 428
E. Preston St., Baltimore, MD 21202) V.1- 1981- Volume(issue)/page/year:
13,155,1993
TYPE OF TEST : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE : Oral
SPECIES OBSERVED : Human - woman
DOSE/DURATION : 28 mg/kg/2W-I
TOXIC EFFECTS :
Gastrointestinal - changes in structure or function of endocrine pancreas
REFERENCE :
LANCAO Lancet. (7 Adam St., London WC2N 6AD, UK) V.1- 1823-
Volume(issue)/page/year: 340,251,1992
TYPE OF TEST : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE : Oral
SPECIES OBSERVED : Human - man
DOSE/DURATION : 2211 mg/kg/37W-I
TOXIC EFFECTS :
Blood - changes in serum composition (e.g. TP, bilirubin, cholesterol)
Biochemical - Enzyme inhibition, induction, or change in blood or tissue
levels - other Enzymes
REFERENCE :
JCPYDR Journal of Clinical Pyschopharmacology. (Williams & Wilkins Co., 428
E. Preston St., Baltimore, MD 21202) V.1- 1981- Volume(issue)/page/year:
15,287,1995
TYPE OF TEST : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE : Oral
SPECIES OBSERVED : Human - man
DOSE/DURATION : 270 mg/kg/6W-I
TOXIC EFFECTS :
Lungs, Thorax, or Respiration - structural or functional change in trachea
or bronchi
Gastrointestinal - hypermotility, diarrhea
Blood - agranulocytosis
REFERENCE :
AMDIBO Annales de Medecine Interne. (Masson Abonnements, B.P.22, F-41354
Vineuil Cedex, France) V.120- 1969- Volume(issue)/page/year:
144,494,1993
TYPE OF TEST : LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE : Oral
SPECIES OBSERVED : Rodent - rat
DOSE/DURATION : 251 mg/kg
TOXIC EFFECTS :
Details of toxic effects not reported other than lethal dose value
REFERENCE :
KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda
Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960-
Volume(issue)/page/year: 7,667,1973
TYPE OF TEST : LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE : Subcutaneous
SPECIES OBSERVED : Rodent - rat
DOSE/DURATION : 240 mg/kg
TOXIC EFFECTS :
Behavioral - altered sleep time (including change in righting reflex)
Behavioral - convulsions or effect on seizure threshold
Lungs, Thorax, or Respiration - respiratory depression
REFERENCE :
KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda
Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960-
Volume(issue)/page/year: 7,667,1973
TYPE OF TEST : LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE : Intravenous
SPECIES OBSERVED : Rodent - rat
DOSE/DURATION : 41600 ug/kg
TOXIC EFFECTS :
Behavioral - convulsions or effect on seizure threshold
Behavioral - ataxia
Lungs, Thorax, or Respiration - respiratory depression
REFERENCE :
KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda
Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960-
Volume(issue)/page/year: 7,667,1973
TYPE OF TEST : LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE : Intramuscular
SPECIES OBSERVED : Rodent - rat
DOSE/DURATION : 210 mg/kg
TOXIC EFFECTS :
Details of toxic effects not reported other than lethal dose value
REFERENCE :
FRPPAO Farmaco, Edizione Pratica. (Casella Postale 227, 27100 Pavia, Italy)
V.8-43 1953-88 For publisher information, see FRMCE8
Volume(issue)/page/year: 26,585,1971
TYPE OF TEST : LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE : Oral
SPECIES OBSERVED : Rodent - mouse
DOSE/DURATION : 150 mg/kg
TOXIC EFFECTS :
Nutritional and Gross Metabolic - body temperature decrease
REFERENCE :
JMCMAR Journal of Medicinal Chemistry. (American Chemical Soc.,
Distribution Office Dept. 223, POB POB 57136, West End Stn., Washington, DC
20037) V.6- 1963- Volume(issue)/page/year: 23,878,1980
TYPE OF TEST : LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE : Intraperitoneal
SPECIES OBSERVED : Rodent - mouse
DOSE/DURATION : 90 mg/kg
TOXIC EFFECTS :
Behavioral - convulsions or effect on seizure threshold
Behavioral - muscle contraction or spasticity
Lungs, Thorax, or Respiration - dyspnea
REFERENCE :
FRPPAO Farmaco, Edizione Pratica. (Casella Postale 227, 27100 Pavia, Italy)
V.8-43 1953-88 For publisher information, see FRMCE8
Volume(issue)/page/year: 26,585,1971
TYPE OF TEST : LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE : Subcutaneous
SPECIES OBSERVED : Rodent - mouse
DOSE/DURATION : 194 mg/kg
TOXIC EFFECTS :
Behavioral - somnolence (general depressed activity)
Behavioral - convulsions or effect on seizure threshold
Behavioral - excitement
REFERENCE :
KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda
Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960-
Volume(issue)/page/year: 7,667,1973
TYPE OF TEST : LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE : Intravenous
SPECIES OBSERVED : Rodent - mouse
DOSE/DURATION : 36500 ug/kg
TOXIC EFFECTS :
Behavioral - somnolence (general depressed activity)
Behavioral - convulsions or effect on seizure threshold
Lungs, Thorax, or Respiration - respiratory depression
REFERENCE :
KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda
Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960-
Volume(issue)/page/year: 7,667,1973
TYPE OF TEST : LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE : Oral
SPECIES OBSERVED : Mammal - dog
DOSE/DURATION : 145 mg/kg
TOXIC EFFECTS :
Gastrointestinal - nausea or vomiting
REFERENCE :
FRPPAO Farmaco, Edizione Pratica. (Casella Postale 227, 27100 Pavia, Italy)
V.8-43 1953-88 For publisher information, see FRMCE8
Volume(issue)/page/year: 26,585,1971
TYPE OF TEST : LD50 - Lethal dose, 50 percent kill
ROUTE OF EXPOSURE : Oral
SPECIES OBSERVED : Rodent - guinea pig
DOSE/DURATION : 510 mg/kg
TOXIC EFFECTS :
Details of toxic effects not reported other than lethal dose value
REFERENCE :
FRPPAO Farmaco, Edizione Pratica. (Casella Postale 227, 27100 Pavia, Italy)
V.8-43 1953-88 For publisher information, see FRMCE8
Volume(issue)/page/year: 26,585,1971
** OTHER MULTIPLE DOSE TOXICITY DATA **
TYPE OF TEST : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE : Oral
SPECIES OBSERVED : Rodent - rat
DOSE/DURATION : 900 mg/kg/30D-I
TOXIC EFFECTS :
Liver - changes in liver weight
Nutritional and Gross Metabolic - weight loss or decreased weight gain
REFERENCE :
KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda
Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960-
Volume(issue)/page/year: 7,674,1973
TYPE OF TEST : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE : Oral
SPECIES OBSERVED : Rodent - rat
DOSE/DURATION : 3650 mg/kg/1Y-I
TOXIC EFFECTS :
Behavioral - somnolence (general depressed activity)
Liver - other changes
Nutritional and Gross Metabolic - weight loss or decreased weight gain
REFERENCE :
KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda
Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960-
Volume(issue)/page/year: 7,682,1973
TYPE OF TEST : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE : Oral
SPECIES OBSERVED : Mammal - dog
DOSE/DURATION : 6320 mg/kg/52W-I
TOXIC EFFECTS :
Sense Organs and Special Senses (Eye) - lacrimation
Behavioral - somnolence (general depressed activity)
Gastrointestinal - changes in structure or function of salivary glands
REFERENCE :
PBPSDY Pharmacological and Biochemical Properties of Drug Substances.
(American Pharmaceutical Assoc., 2215 Constitution Ave., NW, Washington, DC
20037) V.1- 1977- Volume(issue)/page/year: 1,1,1977
TYPE OF TEST : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE : Oral
SPECIES OBSERVED : Primate - monkey
DOSE/DURATION : 14560 mg/kg/2Y-I
TOXIC EFFECTS :
Sense Organs and Special Senses (Eye) - ptosis
Behavioral - somnolence (general depressed activity)
Cardiac - other changes
REFERENCE :
PBPSDY Pharmacological and Biochemical Properties of Drug Substances.
(American Pharmaceutical Assoc., 2215 Constitution Ave., NW, Washington, DC
20037) V.1- 1977- Volume(issue)/page/year: 1,1,1977
** REPRODUCTIVE DATA **
TYPE OF TEST : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE : Oral
SPECIES OBSERVED : Rodent - rat
DOSE : 1080 mg/kg
SEX/DURATION : female 16-22 day(s) after conception
lactating female 20 day(s) post-birth
TOXIC EFFECTS :
Reproductive - Effects on Newborn - viability index (e.g., # alive at day 4
per # born alive)
Reproductive - Effects on Newborn - weaning or lactation index (e.g., #
alive at weaning per # alive at day 4)
Reproductive - Effects on Newborn - growth statistics (e.g.%, reduced weight
gain)
REFERENCE :
FRPPAO Farmaco, Edizione Pratica. (Casella Postale 227, 27100 Pavia, Italy)
V.8-43 1953-88 For publisher information, see FRMCE8
Volume(issue)/page/year: 26,585,1971
TYPE OF TEST : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE : Oral
SPECIES OBSERVED : Rodent - rat
DOSE : 24 mg/kg
SEX/DURATION : female 9-14 day(s) after conception
TOXIC EFFECTS :
Reproductive - Fertility - pre-implantation mortality (e.g. reduction in
number of implants per female; total number of implants per corpora lutea)
Reproductive - Specific Developmental Abnormalities - musculoskeletal system
Reproductive - Effects on Newborn - weaning or lactation index (e.g., #
alive at weaning per # alive at day 4)
REFERENCE :
KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda
Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960-
Volume(issue)/page/year: 7,696,1973
TYPE OF TEST : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE : Oral
SPECIES OBSERVED : Rodent - rat
DOSE : 96 mg/kg
SEX/DURATION : female 9-14 day(s) after conception
TOXIC EFFECTS :
Reproductive - Effects on Newborn - live birth index (measured after birth)
REFERENCE :
KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda
Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960-
Volume(issue)/page/year: 7,696,1973
TYPE OF TEST : TDLo - Lowest published toxic dose
ROUTE OF EXPOSURE : Oral
SPECIES OBSERVED : Rodent - mouse
DOSE : 48 mg/kg
SEX/DURATION : female 7-12 day(s) after conception
TOXIC EFFECTS :
Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death,
e.g., stunted fetus)
REFERENCE :
KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda
Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960-
Volume(issue)/page/year: 7,696,1973
** MUTATION DATA **
TYPE OF TEST : Sex chromosome loss and nondisjunction
ROUTE OF EXPOSURE : Oral
TEST SYSTEM : Insect - Drosophila melanogaster
DOSE/DURATION : 2 mg/2D
REFERENCE :
SOGEBZ Soviet Genetics. English translation of GNKAA5. (Plenum Pub. Corp.,
233 Spring St., New York, NY 10013) V.2- 1966- Volume(issue)/page/year:
11,718,1975
TYPE OF TEST : Cytogenetic analysis
TEST SYSTEM : Human Lymphocyte
DOSE/DURATION : 10 mg/L
REFERENCE :
HUGEDQ Human Genetics. (Springer-Verlag New York, Inc., Service Center, 44
Hartz Way, Secaucus, NJ 07094) V.31- 1976- Volume(issue)/page/year:
38,77,1977
*** REVIEWS ***
TOXICOLOGY REVIEW
PBPSDY Pharmacological and Biochemical Properties of Drug Substances.
(American Pharmaceutical Assoc., 2215 Constitution Ave., NW, Washington, DC
20037) V.1- 1977- Volume(issue)/page/year: 1,1,1977
*** END OF RECORD ***