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Piperazine, 1 - acetyl - 4 - (4 - ( (2 - (2,4 - dichlorophenyl) - 2 - (1H - imidazol - 1 - ylmethyl) - 1,3 - dioxolan - 4 - yl) methoxy) phenyl) - , cis -

RTECS #: TK7912300

CAS #: 65277-42-1

UPDATE: May 2009 MW: 531.48 MF: C26H28Cl2N4O4


NOTE:

TABLE OF CONTENTS:
  1. SYNONYMS:
  2. MUTATION DATA:
  3. REPRODUCTIVE EFFECTS DATA:
  4. ACUTE TOXICITY DATA:
  5. OTHER MULTIPLE DOSE DATA:
  6. REVIEWS:
  7. NIOSH DOCUMENTATION AND SURVEILLANCE:
  8. REFERENCES:

SYNONYMS:

  1. Fungarest
  2. Fungoral
  3. KW - 1414
  4. Keto
  5. Ketoconazol
  6. Ketoconazole
  1. Ketoderm
  2. Ketoisdin
  3. Nizoral
  4. Orifungal M
  5. Panfungol
  6. R 41400


SKIN AND EYE IRRITATION DATA AND REFERENCES:

ROUTE/
ORGANISM 		DOSE
EFFECT

 REFERENCE
N/R
 N/R N/R N/R


MUTATION DATA AND REFERENCES:

SYSTEM TEST ROUTE/
ORGANISM/
TISSUE 		DOSE REFERENCE
DNA inhibition human lymphocyte 10 mg/L AMACCQ 24,478,1983
DNA inhibition human other cell types 1 µmol/L TUMOAB 77,385,1991


REPRODUCTIVE EFFECTS DATA AND REFERENCES:

ROUTE/
ORGANISM 		DOSE
EFFECT

 REFERENCE
oral
man 		lowest published toxic dose: 1,029 mg/kg (60 day male) Reproductive: Other effects on male

Endocrine: Androgenic 		ACENA7 110,276,1985
oral
mouse 		lowest published toxic dose: 300 mg/kg (1 day male) Reproductive: Paternal effects: Spermatogenesis (including genetic material, sperm morphology, motility, and count) JOAND3 13,191,1992
oral
rat 		lowest published toxic dose: 6,480 mg/kg (9 week male/2 week prior to copulation-7 day pregnant) Reproductive: Effects on fertility: Mating performance (e.g., # sperm positive females per # females mated; # copulations per # estrus cycles)

Reproductive: Effects on fertility: Female fertility index (e.g., # females pregnant per # sperm positive females; # females pregnant per # females mated) 		KSRNAM 18,1433,1984
oral
rat 		lowest published toxic dose: 600 mg/kg (3 day male) Reproductive: Paternal effects: Spermatogenesis (including genetic material, sperm morphology, motility, and count)

Reproductive: Effects on fertility: Male fertility index (e.g., # males impregnating females per # males exposed to fertile nonpregnant females) 		CCPTAY 41,411,1990
oral
rat 		lowest published toxic dose: 3,240 mg/kg (9 week male/2 week prior to copulation-7 day pregnant) Reproductive: Effects on fertility: Pre- implantation mortality (e.g., reduction in number of implants per female; total number of implants per corpora lutea)

Reproductive: Effects on fertility: Litter size (e.g., # fetuses per litter; measured before birth) 		KSRNAM 18,1433,1984
oral
rat 		lowest published toxic dose: 880 mg/kg (7-17 day pregnant) Reproductive: Effects on fertility: Litter size (e.g., # fetuses per litter; measured before birth)

Reproductive: Effects on embryo or fetus: Fetal death

Reproductive: Specific developmental abnormalities: Musculoskeletal system 		KSRNAM 18,1433,1984
oral
rat 		lowest published toxic dose: 1,040 mg/kg (17-21 day pregnant/21 day after birth) Reproductive: Maternal effects: Parturition

Reproductive: Effects on newborn: Viability index (e.g., # alive at day 4 per # born alive) 		KSRNAM 18,1433,1984
oral
rat 		lowest published toxic dose: 300 mg/kg (1 day male) Reproductive: Other effects on male JOAND3 13,191,1992
oral
rat 		lowest published toxic dose: 520 mg/kg (6-18 day pregnant) Reproductive: Other effects on female

Reproductive: Effects on fertility: Litter size (e.g., # fetuses per litter; measured before birth)

Reproductive: Effects on embryo or fetus: Fetal death 		KSRNAM 18,1433,1984
oral
rat 		lowest published toxic dose: 80 mg/kg (1-8 day pregnant) Reproductive: Effects on fertility: Post- implantation mortality (e.g., dead and/or resorbed implants per total number of implants) HBPTO* 1,736,2001
oral
rat 		lowest published toxic dose: 175 mg/kg (28 day male) Reproductive: Paternal effects: Prostate, seminal vesicle, Cowper's gland, accessory glands ARTODN 80,797,2006
oral
rat 		lowest published toxic dose: 2,800 mg/kg (28 day male) Reproductive: Paternal effects: Testes, epididymis, sperm duct

Reproductive: Paternal effects: Prostate, seminal vesicle, Cowper's gland, accessory glands 		ARTODN 80,797,2006
oral
rat 		lowest published toxic dose: 175 mg/kg (28 day prior to copulation) Reproductive: Maternal effects: Uterus, cervix, vagina ARTODN 80,797,2006
oral
rat 		lowest published toxic dose: 1,400 mg/kg (28 day prior to copulation) Reproductive: Maternal effects: Ovaries, fallopian tubes ARTODN 80,797,2006
oral
rat 		lowest published toxic dose: 2,800 mg/kg (28 day prior to copulation) Reproductive: Maternal effects: Uterus, cervix, vagina

Reproductive: Maternal effects: Menstrual cycle changes or disorders 		ARTODN 80,797,2006


TUMORIGENIC DATA AND REFERENCES:

ROUTE/
ORGANISM 		DOSE
EFFECT

 REFERENCE
N/R
 N/R N/R N/R


ACUTE TOXICITY DATA AND REFERENCES:

ROUTE/
ORGANISM 		DOSE
EFFECT

 REFERENCE
intraduodenal
rat 		lowest published toxic dose: 50 mg/kg Liver: Other changes

Biochemical: Metabolism (intermediary): Lipids including transport 		BJPCBM 138,1459,2003
intraperitoneal
mouse 		lethal dose (50 percent kill): 2,937 mg/kg N/R IYKEDH 18,474,1987
intraperitoneal
rat 		lethal dose (50 percent kill): 1,474 mg/kg N/R IYKEDH 18,474,1987
intraperitoneal
rat 		lowest published toxic dose: 100 mg/kg Liver: Hepatitis (hepatocellular necrosis), zonal

Blood: Changes in serum composition (e.g. TP, bilirubin, cholesterol)

Biochemical: Enzyme inhibition, induction, or change in blood or tissue levels: Transaminases 		TXCYAC 208,367,2005
intravenous
dog 		lethal dose (50 percent kill): 23,300 µg/kg N/R MDACAP 17,373,1981
intravenous
guinea pig 		lethal dose (50 percent kill): 23,300 µg/kg N/R MDACAP 17,373,1981
intravenous
mouse 		lethal dose (50 percent kill): 32 mg/kg N/R AMACCQ 33,895,1989
intravenous
rat 		lethal dose (50 percent kill): 86 mg/kg N/R DRUGAY 23,1,1982
oral
child 		lowest published toxic dose: 450 mg/kg/90 day- intermittent Endocrine: Evidence of thyroid hypofunction

Nutritional and Gross Metabolic: Other changes 		BMJOAE 293,993,1986
oral
dog 		lethal dose (50 percent kill): 178 mg/kg N/R MDACAP 17,373,1981
oral
guinea pig 		lethal dose (50 percent kill): 178 mg/kg N/R MDACAP 17,373,1981
oral
human 		lowest published toxic dose: 8.6 mg/kg Endocrine: Androgenic

Biochemical: Metabolism (intermediary): Other 		AIMDAP 145,1429,1985
oral
human 		lowest published toxic dose: 2.8 mg/kg Endocrine: Androgenic

Endocrine: Change in LH 		AIMDAP 142,2137,1982
oral
human 		lowest published toxic dose: 2.857 mg/kg Immunological Including Allergic: Anaphylaxis (multiple organ involvement) BMJOAE 287,,1983
oral
man 		lowest published lethal dose: 45 mg/kg/17 day- intermittent Behavioral: Coma

Liver: Jaundice, other or unclassified 		GUTTAK 26,636,1986
oral
man 		lowest published toxic dose: 49 mg/kg/17 day- intermittent Liver: Other changes GASTAB 86,503,1984
oral
man 		lowest published toxic dose: 5.7 mg/kg Endocrine: Androgenic

Endocrine: Other changes 		ACENA7 105,275,1984
oral
mouse 		lethal dose (50 percent kill): 618 mg/kg N/R MDACAP 17,373,1981
oral
rat 		lethal dose (50 percent kill): 166 mg/kg N/R MDACAP 17,373,1981
oral
rat 		lowest published toxic dose: 24 mg/kg Endocrine: Androgenic

Reproductive: Paternal effects: Spermatogenesis (including genetic material, sperm morphology, motility, and count) 		ACENA7 111,246,1986
oral
rat 		lowest published toxic dose: 227 mg/kg Kidney, Ureter, and Bladder: Other changes TXCYAC 246,91,2008
oral
rabbit 		lowest published toxic dose: 40 mg/kg Biochemical: Enzyme inhibition, induction, or change in blood or tissue levels: Transaminases ACPSI* 24,778,2003
oral
woman 		lowest published lethal dose: 412 mg/kg/15 week- intermittent Behavioral: Coma

Liver: Hepatitis (hepatocellular necrosis), diffuse

Liver: Jaundice, other or unclassified 		GUTTAK 26,636,1986
oral
woman 		lowest published lethal dose: 264 mg/kg/66 day- intermittent Liver: Other changes GASTAB 86,503,1984
oral
woman 		lowest published toxic dose: 60 mg/kg Liver: Other changes GASTAB 86,503,1984
subcutaneous
mouse 		lethal dose (50 percent kill): >4 gm/kg N/R IYKEDH 18,474,1987
subcutaneous
rat 		lethal dose (50 percent kill): >2,400 mg/kg N/R IYKEDH 18,474,1987
unreported route
rat 		lowest published toxic dose: 40 mg/kg Liver: Other changes

Biochemical: Enzyme inhibition, induction, or change in blood or tissue levels: Transaminases 		TOXID9 60,168,2001


OTHER MULTIPLE DOSE DATA AND REFERENCES:

ROUTE/
ORGANISM 		DOSE
EFFECT

 REFERENCE
intraperitoneal
mouse 		lowest published toxic dose: 900 mg/kg/6 week- intermittent Tumorigenic: Active as anti-cancer agent

Nutritional and Gross Metabolic: Other changes 		MOCAE8 34,199,2002
intraperitoneal
rat 		lowest published toxic dose: 600 mg/kg/4 day- intermittent Liver: Changes in liver weight

Nutritional and Gross Metabolic: Weight loss or decreased weight gain 		TOSCF2 46,45,1998
intraperitoneal
rat 		lowest published toxic dose: 2,250 mg/kg/15 day- intermittent Liver: Changes in liver weight

Endocrine: Androgenic

Nutritional and Gross Metabolic: Weight loss or decreased weight gain 		TOSCF2 46,45,1998
intraperitoneal
rat 		lowest published toxic dose: 500 mg/kg/5 day- intermittent Reproductive: Paternal effects: Spermatogenesis (including genetic material, sperm morphology, motility, and count)

Biochemical: Enzyme inhibition, induction, or change in blood or tissue levels: Multiple enzyme effects

Related to Chronic Data: Changes in testicular weight 		ETPAEK 59,377,2007
oral
dog 		lowest published toxic dose: 1,200 mg/kg/30 day- intermittent Liver: Other changes

Liver: Changes in liver weight 		KSRNAM 18,1426,1984
oral
dog 		lowest published toxic dose: 280 mg/kg/7 day- intermittent Reproductive: Paternal effects: Testes, epididymis, sperm duct

Biochemical: Metabolism (intermediary): Other proteins 		TOXID9 72,12,2003
oral
human 		lowest published toxic dose: 154.3 mg/kg/9 day- intermittent Endocrine: Androgenic

Biochemical: Metabolism (intermediary): Other 		AIMDAP 145,1429,1985
oral
human 		lowest published toxic dose: 1,539 mg/kg/90 day- intermittent Endocrine: Gynecomastia AIMDAP 145,1429,1985
oral
man 		lowest published toxic dose: 240 mg/kg/3 week- intermittent Endocrine: Other changes

Blood: Changes in serum composition (e.g. TP, bilirubin, cholesterol)

Biochemical: Metabolism (intermediary): Other proteins 		NEROEW 28,379,2003
oral
mouse 		lowest published toxic dose: 24,000 mg/kg/60 day- continuous Reproductive: Paternal effects: Spermatogenesis (including genetic material, sperm morphology, motility, and count) HBPTO* 1,736,2001
oral
mouse 		lowest published toxic dose: 1,749 ng/kg/7 day- intermittent Liver: Other changes

Liver: Changes in liver weight

Biochemical: Enzyme inhibition, induction, or change in blood or tissue levels: Hepatic microsomal mixed oxidase (dealkylation, hydroxylation, etc.) 		TXCYAC 94,81,1994
oral
mouse 		lowest published toxic dose: 3,125 ng/kg/21 day- intermittent Liver: Other changes TXCYAC 94,81,1994
oral
rat 		lowest published toxic dose: 600 mg/kg/3 day- continuous Reproductive: Paternal effects: Spermatogenesis (including genetic material, sperm morphology, motility, and count) HBPTO* 1,736,2001
oral
rat 		lowest published toxic dose: 80 mg/kg/8 day- continuous Endocrine: Other changes

Related to Chronic Data: Changes in uterine weight 		HBPTO* 1,736,2001
oral
rat 		lowest published toxic dose: 480 mg/kg/20 day- intermittent Nutritional and Gross Metabolic: Weight loss or decreased weight gain TOSCF2 60,285,2001
oral
rat 		lowest published toxic dose: 720 mg/kg/30 day- intermittent Reproductive: Paternal effects: Testes, epididymis, sperm duct TOSCF2 60,285,2001
oral
rat 		lowest published toxic dose: 750 mg/kg/30 day- intermittent Reproductive: Other effects on male TOXID9 72,131,2003
oral
rat 		lowest published toxic dose: 375 mg/kg/15 day- intermittent Endocrine: Change in gonadotropins TOSCF2 69,79,2002
oral
rat 		lowest published toxic dose: 1,125 mg/kg/15 day- intermittent Liver: Changes in liver weight

Endocrine: Change in gonadotropins 		TOSCF2 69,79,2002
oral
rat 		lowest published toxic dose: 1,500 mg/kg/15 day- intermittent Liver: Changes in liver weight

Endocrine: Change in gonadotropins

Related to Chronic Data: Changes in prostate weight 		TOSCF2 69,79,2002
oral
rat 		lowest published toxic dose: 700 mg/kg/28 day- intermittent Endocrine: Estrogenic ARTODN 80,797,2006
oral
rat 		lowest published toxic dose: 2,800 mg/kg/28 day- intermittent Endocrine: Changes in adrenal weight

Related to Chronic Data: Changes in prostate weight 		ARTODN 80,797,2006
oral
rat 		lowest published toxic dose: 175 mg/kg/28 day- intermittent Related to Chronic Data: Changes in uterine weight ARTODN 80,797,2006
oral
rat 		lowest published toxic dose: 1,400 mg/kg/28 day- intermittent Endocrine: Changes in adrenal weight

Related to Chronic Data: Changes in ovarian weight 		ARTODN 80,797,2006
oral
rat 		lowest published toxic dose: 2,800 mg/kg/28 day- intermittent Cardiac: Changes in heart weight

Endocrine: Estrogenic

Nutritional and Gross Metabolic: Weight loss or decreased weight gain 		ARTODN 80,797,2006
oral
rat 		lowest published toxic dose: 2,800 mg/kg/28 day- intermittent Liver: Changes in liver weight

Kidney, Ureter, and Bladder: Changes in kidney weight

Endocrine: Evidence of thyroid hypofunction 		ARTODN 80,797,2006
oral
rat 		lowest published toxic dose: 1,135 mg/kg/5 day- intermittent Liver: Other changes

Biochemical: Metabolism (intermediary): Effect on inflammation or mediation of inflammation 		TXCYAC 246,91,2008
oral
woman 		lowest published toxic dose: 20 mg/kg/2 day- intermittent Vascular: BP lowering not characterized in autonomic section

Vascular: Regional or general arteriolar or venous dilation

Immunological Including Allergic: Anaphylaxis (multiple organ involvement) 		APHRER 39,547,2005
subcutaneous
rat 		lowest published toxic dose: 350 mg/kg/14 day- intermittent Endocrine: Androgenic RTOPDW 26,60,1997
subcutaneous
rat 		lowest published toxic dose: 700 mg/kg/14 day- intermittent Reproductive: Paternal effects: Prostate, seminal vesicle, Cowper's gland, accessory glands

Nutritional and Gross Metabolic: Weight loss or decreased weight gain 		RTOPDW 26,60,1997
unreported route
man 		lowest published toxic dose: 77,100 mg/kg/27 day- intermittent Behavioral: Headache

Liver: Jaundice, other or unclassified

Kidney, Ureter, and Bladder: Other changes in urine composition 		DDSCDJ 33,240,1988
unreported route
rat 		lowest published toxic dose: 144 mg/kg/12 day- continuous Reproductive: Maternal effects: Parturition

Endocrine: Other changes 		HBPTO* 1,736,2001


REVIEWS:

ORGANIZATION STANDARD
REFERENCE
TOXICOLOGY REVIEW
ARPTDI 43,441,2003
TOXICOLOGY REVIEW
TOLED5 127,279,2002
TOXICOLOGY REVIEW
MUREAV 488,151,2001
TOXICOLOGY REVIEW
TPHSDY 23,355,2002
TOXICOLOGY REVIEW
TPHSDY 24,161,2003
TOXICOLOGY REVIEW
JHEPT* 3,399,1986
TOXICOLOGY REVIEW
DIMON* 39,678,1993
TOXICOLOGY REVIEW
ENTOX* -,384,2005
TOXICOLOGY REVIEW
PSBUL* 35,66,2001
TOXICOLOGY REVIEW
PSBUL* 36,91,2002
TOXICOLOGY REVIEW
HTOPA* 1,501,2002


STANDARDS AND REGULATIONS:

ORGANIZATION STANDARD
REFERENCE
N/R N/R N/R


NIOSH DOCUMENTATION AND SURVEILLANCE:

ORGANIZATION STANDARD or SURVEY
REFERENCE
National Occupational Exposure Survey 1983 National Occupational Exposure Survey 1983: Hazard Code: X6059;
Number of Industries 1;
Total Number of Facilities 30;
Number of Occupations 3;
Total Number of Employees Exposed 1,045;
Total Number of Female Employees Exposed 620


STATUS IN FEDERAL AGENCIES:

ORGANIZATION
REFERENCE
N/R


REFERENCES:

CODEN
REFERENCE
ACENA7 Acta Endocrinologica (Copenhagen). (Periodica, Skolegade 12 E, DK-2500 Valby, Denmark) V.1- 1948-
ACPSI* Acta pharmacologica Sinica (Shanghai : Shanghai Institute of Materia Medica : Chinese Academy of Science ; Carlton, VIC, Australia : Blackwell Publishing Asia, 2005) V.21- 2000-
AIMDAP Archives of Internal Medicine. (AMA, 535 N. Dearborn St., Chicago, IL 60610) V.1- 1908-
AMACCQ Antimicrobial Agents and Chemotherapy. (American Soc. for Microbiology, 1913 I St., NW, Washington, DC 20006) V.1- 1972-
APHRER Annals of Pharmacotherpy. (Harvey Whitney Books Co., POB 42696, Cincinnati, OH 45242) V. 26- 1992-
ARPTDI Annual Review of Pharmacology and Toxicology. (Annual Reviews, Inc., POB 10139, Palo Alto, CA 94303) V.16- 1976-
ARTODN Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974-
BJPCBM British Journal of Pharmacology. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.34- 1968-
BMJOAE British Medical Journal. (British Medical Assoc., BMA House, Tavistock Sq., London WC1H 9JR, UK) V.1- 1857-
CCPTAY Contraception. (Geron-X, Inc., POB 1108, Los Altos, CA 94022) V.1- 1970-
DDSCDJ Digestive Diseases and Sciences. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) V.24- 1979-
DIMON* Disease-a Month (Chicago : Year Book Publishers) V. 24- 1978-
DRUGAY Drugs. International Journal of Current Therapeutics and Applied Pharmacology Reviews. (ADIS Press International Inc., Suite B-30, Oxford Ct. Business Center, 582 Middletown Blvd., Langhorne, PA 19047) V.1- 1971-
ENTOX* Encyclopedia of Toxicology: Reference Book, Elsevier, 2005
ETPAEK Experimental and Toxicologic Pathology. (Gustav Fischer Verlag Jena, Postfach 100537, D-07705 Jena, Germany) V.44- 1992-
GASTAB Gastroenterology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1943-
GUTTAK Gut. (British Medical Journal, Box 560B, Kennebunkport, ME 04046) V.1- 1960-
HBPTO* Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001
HTOPA*
IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970-
JHEPT* Journal of Hepatology: Official Journal of the European Association for the Study of the Liver (EASL) (Elsevier) V.1- 1985-
JOAND3 Journal of Andrology. (Lippincott/Harper, Journal Fulfillment Dept., 2350 Virginia Ave., Hagerstown, MD 21740) V.1- 1980-
KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960-
MDACAP Medicamentos de Actualidad. (J.R. Prous, S.A., Apartado de Correos 540, 08080 Barcelona, Spain) V.1- 1965-
MOCAE8 Molecular Carcinogenesis. (John Wiley & Sons, 605 Third Avenue, New York, NY 10158) V.1- 1988-
MUREAV Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964-
NEROEW Neuropsychopharmacology. (Elsevier Science, 655 Avenue of the Americas, New York, NY 10010) V.1- 1987-
PSBUL*
RTOPDW Regulatory Toxicology and Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1981-
TOLED5 Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977-
TOSCF2 Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998-
TOXID9 Toxicologist. (Soc. of Toxicology, Inc., 475 Wolf Ledge Parkway, Akron, OH 44311) V.1- 1981-
TPHSDY Trends in Pharmacological Sciences. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1979-
TUMOAB Tumori. (Casa Editrice Ambrosiana, Via G. Frua 6, 20146 Milan, Italy) V.1- 1911-
TXCYAC Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973-

Used as an antifungal drug

RTECS Compound Description:
   Agricultural Chemical
   Drug
   Mutagen
   Reproductive Effector
   Human Data
   Natural Product

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