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Registry of Toxic Effects of Chemical Substances (RTECS)

Caffeine

RTECS #

EV6475000

CAS #

58-08-2

Updated

December 2013

Molecular Weight

194.22

Molecular Formula

C8H10N4O2

Synonyms

1,3,7-Trimethyl-2,6-dioxopurine
1,3,7-Trimethylxanthine
1H-Purine-2,6-dione, 3,7-dihydro-1,3,7-trimethyl-
3,7-Dihydro-1,3,7-trimethyl-1H-purine-2,6-dione
Anhydrous caffeine
Caffein
Caffeina (Italian)
Coffein (German)
Coffeine
Coffeinum
Eldiatric C
Guaranine
Kofein (Czech)
Koffein (German)
Methyltheobromide
NCI-C02733
NO-Doz
Organex
Thein
Theine
Theobromine, 1-methyl-
Theophylline, 7-methyl
Xanthine, 1,3,7-trimethyl

Mutation Data and Reference

System TestRoute/Organism/TissueDoseReference
Cytogenetic Analysis/Other microorganisms5000 ppmIJEBA6 13,387,1975
Cytogenetic Analysisleukocyte/human100 mg/LMUREAV 3,249,1966
Cytogenetic Analysisfibroblast/human2600 µmol/L/24HMUREAV 46,297,1977
Cytogenetic Analysislymphocyte/human100 µg/L/24HMUREAV 48,205,1977
Cytogenetic Analysisembryo/human50 ppm/24HIDZAAW 46,337,1971
Cytogenetic AnalysisHeLa cell/human500 mg/LRBPMB2 10,60,1977
Cytogenetic Analysisoral/mouse14 mg/kg/7D-continuousDCTODJ 17,113,1994
Cytogenetic Analysisintravenous/mouse50 mg/kgMUREAV 60,329,1979
Cytogenetic AnalysisAscites tumor/mouse7700 µmol/LPHARAT 32,178,1977
Cytogenetic Analysislymphocyte/mouse100 mg/LENMUDM 5,383,1983
Cytogenetic Analysisovary/hamster2 mmol/LCGCGBR 41,202,1986
Cytogenetic Analysislung/hamster10 mmol/LHEREAY 69,35,1971
Cytogenetic Analysisother cell types/hamster25 mmol/L/2H-continuousMUREAV 12,463,1971
Cytogenetic Analysisfibroblast/hamster1 gm/LESKHA5 (96),55,1978
Cytogenetic Analysisfibroblast/chicken25 mmol/LNATWAY 59,277,1972
Cytogenetic Analysisintraperitoneal/mouse50 mg/kgETOPFR 15,79,2004
DNA Damagelymphocyte/mammal (species unspecified)100 mmol/LPNASA6 48,686,1962
DNA Damageintraperitoneal/mouse100 mg/kgATSUDG 5,355,1982
DNA Damageleukocyte/mouse100 µmol/LCRNGDP 12,1781,1991
DNA Damage/Escherichia coli1000 ppm/3MMGGEAE 118,373,1972
DNA inhibition/Escherichia coli10 mmol/LCBINA8 40,141,1982
DNA inhibition/Other microorganisms2500 mg/LMGGEAE 150,301,1977
DNA inhibition/Other microorganisms30 mmol/LCRNGDP 3,151,1982
DNA inhibition/Other microorganisms10 mmol/LCRNGDP 3,151,1982
DNA inhibitionother cell types/rat200 µmol/LREXMAS 192,115,1992
DNA inhibitionHeLa cell/human1 mmol/LRAREAE 37,334,1969
DNA inhibitionother cell types/human4 mmol/LBIOJAU 35,665,1981
DNA inhibitionintraperitoneal/mouse50 mg/kgIJEBA6 20,433,1982
DNA inhibitionoral/mouse208 mg/kg/7D-continuousIJEBA6 22,608,1984
DNA inhibitionlymphocyte/mouse5 mmol/LMUREAV 26,73,1974
DNA inhibitionfibroblast/mouse5 mmol/LMUREAV 26,73,1974
DNA inhibitionlung/hamster1 mmol/LCNREA8 33,2444,1973
DNA inhibitionlymphocyte/mammal (species unspecified)10 mmol/LCRNGDP 3,151,1982
DNA inhibitionfibroblast/human2 mmol/L/6HMUREAV 532,85,2003
DNA repair/Escherichia coli10 pphAGACBH 4,286,1974
DNA repairfibroblast/human750 µmol/LASMACK 75,107,1975
DNA repair/Salmonella typhimurium10 pphAGACBH 4,286,1974
DNA repair/Bacillus subtilis1 gm/LMUREAV 16,165,1972
Dominant Lethal Testoral/mouse2520 mg/kg/1W-continuousDMWOAX 92,2315,1967
gene conversion and mitotic recombination/Saccharomyes cerevisiae10 pphAGACBH 4,286,1974
gene conversion and mitotic recombination/Schizosaccharomyces pombe1000 ppmMUREAV 26,83,1974
host-mediated assayAscites tumor/mouse150 mg/kgMUREAV 243,109,1990
micronucleus testoral/hamster300 mg/kgMUREAV 174,53,1986
micronucleus testkidney/rat10 mmol/LMUREAV 189,299,1987
micronucleus testlung/hamster2000 mg/L/6H (-enzymatic activation step)MUREAV 721,21,2011
micronucleus testmultiple/non-mammalian species100 ppm/8D-continuousMUREAV 125,275,1984
micronucleus testembryo/mouse7 mmol/LTCMUD8 5,123,1985
micronucleus testoral/mouse100 mg/kgMUREAV 174,53,1986
morphological transformembryo/rat320 µg/plateJJATDK 1,190,1981
morphological transformembryo/hamster125 mg/LCBINA8 13,105,1976
mutation in mammalian somatic cellslymphocyte/mouse500 mg/LENMUDM 5,383,1983
mutation in microorganisms/Klebsiella pneumoniae2 gm/L (-enzymatic activation step)EXPEAM 25,85,1969
mutation in microorganisms/Other microorganisms2000 ppm (-enzymatic activation step)HEREAY 36,134,1950
mutation in microorganisms/Other microorganisms400 mg/L (-enzymatic activation step)MUREAV 43,37,1977
mutation in microorganisms/Escherichia coli6000 ppm/48H (-enzymatic activation step)AMNTA4 85,119,1951
mutation in microorganisms/Bacillus subtilis2500 mg/L (-enzymatic activation step)MUREAV 117,55,1983
other mutation test systems/Escherichia coli1500 mg/LMILEDM 26,7,1984
other mutation test systems/Other microorganisms1 pphIJEBA6 13,387,1975
other mutation test systemslymphocyte/human1 mmol/LMUREAV 15,197,1972
other mutation test systemsintraperitoneal/mouse50 mg/kgIJEBA6 20,433,1982
sex chromosome loss and nondisjunction/Saccharomyes cerevisiae250 mg/LEVHPAZ 31,97,1979
sex chromosome loss and nondisjunctionoral/Drosophila melanogaster5000 ppmGENEA3 44,146,1973
sex chromosome loss and nondisjunctionparenteral/Drosophila melanogaster5000 ppmAMNTA4 93,135,1959
sex chromosome loss and nondisjunction/Neurospora crassa750 mg/LMUREAV 167,35,1986
sister chromatid exchangelymphocyte/human1 mmol/LHEREAY 91,135,1979
sister chromatid exchangeintravenous/mouse50 mg/kgMUREAV 60,329,1979
sister chromatid exchangeoral/mouse5 gm/kg/5D-continuousMUREAV 122,347,1983
sister chromatid exchangeother cell types/mouse100 µmol/LTJADAB 32,213,1985
sister chromatid exchangelung/hamster4 mmol/LMUREAV 174,21,1986
sister chromatid exchangeoral/hamster300 mg/kgMUREAV 174,53,1986
specific locus testintraperitoneal/mouse35 mg/kgENMUDM 1,120,1979
specific locus testoral/Drosophila melanogaster3000 ppmFCTOD7 24,835,1986
Unscheduled DNA Synthesisother cell types/human1 mmol/LBIOJAU 35,665,1981

Reproductive Effects Data and References

Route/OrganismDoseEffectReference
intraperitoneal/mouse 250 mg/kg (10D pregnant)Reproductive: Effects on embryo or fetus: Fetal deathKAIZAN 36,521,1961
intraperitoneal/mouse 500 mg/kg (11-12D pregnant)Reproductive: Effects on fertility: Post- implantation mortality (e.g., dead and/or resorbed implants per total number of implants)

Reproductive: Other developmental abnormalities
TJADAB 28,427,1983
intraperitoneal/mouse 200 mg/kg (12D pregnant)Reproductive: Effects on fertility: Post- implantation mortality (e.g., dead and/or resorbed implants per total number of implants)

Reproductive: Effects on embryo or fetus: Fetotoxicity (except death, e.g., stunted fetus)

Reproductive: Specific developmental abnormalities: Craniofacial (including nose and tongue)
JJPAAZ 19,134,1969
intraperitoneal/mouse 200 mg/kg (12D pregnant)Reproductive: Specific developmental abnormalities: Musculoskeletal system

Reproductive: Other developmental abnormalities
JJPAAZ 19,134,1969
intraperitoneal/rat 420 mg/kg (1-21D pregnant)Reproductive: Effects on fertility: Post- implantation mortality (e.g., dead and/or resorbed implants per total number of implants)

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

Reproductive: Effects on embryo or fetus: Fetotoxicity (except death, e.g., stunted fetus)
JRPFA4 34,495,1973
intraperitoneal/rat 75 mg/kg (12D pregnant)Reproductive: Specific developmental abnormalities: Central nervous system

Reproductive: Specific developmental abnormalities: Eye, ear
TJADAB 25,95,1982
intravenous/mouse 200 mg/kg (13D pregnant)Reproductive: Specific developmental abnormalities: Craniofacial (including nose and tongue)

Reproductive: Other developmental abnormalities
JJPAAZ 26,751,1976
intravenous/rat 37500 µg/kg (11D pregnant)Reproductive: Effects on embryo or fetus: Fetotoxicity (except death, e.g., stunted fetus)TJADAB 25(2),54A,1982
intravenous/rat 25 mg/kg (6D pregnant)Reproductive: Specific developmental abnormalities: Musculoskeletal systemANANAU 168,109,1989
intravenous/rat 113 mg/kg (11D pregnant)Reproductive: Specific developmental abnormalities: Musculoskeletal systemTOXID9 3,65,1983
multiple/mouse 408 mg/kg (9W prior to copulation/12D pregnant)Reproductive: Specific developmental abnormalities: Skin and skin appendagesSEIJBO 6,171,1966
oral/hamster 8160 mg/kg (60D male)Reproductive: Effects on newborn: Sex ratioJRPFA4 43,141,1975
oral/rat 2975 mg/kg (multigeneration)Reproductive: Effects on fertility: Litter size (e.g., # fetuses per litter; measured before birth)

Reproductive: Effects on newborn: Growth statistics (e.g., reduced weight gain)
TOXID9 30,121,1996
oral/rat 11900 mg/kg (multigeneration)Reproductive: Effects on embryo or fetus: Fetal deathTOXID9 30,121,1996
oral/mouse 3.26 gm/kg (7D male/7D prior to copulation/21D pregnant)Reproductive: Effects on newborn: Sex ratioNTIS** #PB85101202/AS
oral/mouse 4 gm/kg (1W male/12W prior to copulation)Reproductive: Effects on newborn: Live birth index (Litter size (e.g., # fetuses per litter; measured after birth)NTIS** #PB85101202/AS
oral/rat 12.5 mg/kg (multigenerations)Reproductive: Effects on newborn: Growth statistics (e.g., reduced weight gain)NTIS** #PB96-211743
oral/rat 25 mg/kg (multigenerations)Reproductive: Specific developmental abnormalities: Urogenital systemNTIS** #PB96-211743
oral/mouse 88 mg/kg (multigenerations)Reproductive: Specific developmental abnormalities: Hepatobiliary system

Reproductive: Effects on newborn: Growth statistics (e.g., reduced weight gain)
NTIS** #PB85101202/AS
oral/rat 437.5 mg/kg (7D male/7D prior to copulation/21D pregnant)Reproductive: Effects on newborn: Other neonatal measures or effectsNTIS** #PB96-211743
oral/mouse 770 mg/kg (7D male/7D prior to copulation/21D pregnant)Reproductive: Effects on newborn: Live birth index (Litter size (e.g., # fetuses per litter; measured after birth)NTIS** #PB85101202/AS
oral/rat 50 mg/kg (multigenerations)Reproductive: Effects on newborn: Live birth index (Litter size (e.g., # fetuses per litter; measured after birth)NTIS** #PB96-211743
oral/woman 84 mg/kg (1-42D pregnant)Reproductive: Effects on fertility: AbortionNEJMAG 343,1839,2000
oral/mouse 2.16 mg/kg (7D preg-21D after birth)Reproductive: Effects on newborn: Growth statistics (e.g., reduced weight gain)

Reproductive: Effects on newborn: Behavioral
TXCYAC 241,119,2007
oral/mouse 1 gm/kg (8-12D pregnant)Reproductive: Effects on newborn: Growth statistics (e.g., reduced weight gain)JTEHD6 10,541,1982
oral/mouse 350 mg/kg (8D pregnant)Reproductive: Specific developmental abnormalities: Musculoskeletal systemTCMUD8 5,3,1985
oral/mouse 1650 mg/kg (6-16D pregnant)Reproductive: Specific developmental abnormalities: Central nervous system

Reproductive: Specific developmental abnormalities: Craniofacial (including nose and tongue)

Reproductive: Specific developmental abnormalities: Musculoskeletal system
TXCYAC 23,57,1982
oral/mouse 1650 mg/kg (6-16D pregnant)Reproductive: Effects on fertility: Post- implantation mortality (e.g., dead and/or resorbed implants per total number of implants)

Reproductive: Effects on embryo or fetus: Fetotoxicity (except death, e.g., stunted fetus)
TXCYAC 23,57,1982
oral/mouse 2691 mg/kg (5-18D pregnant)Reproductive: Other developmental abnormalitiesTXCYAC 23,57,1982
oral/woman 6750 mg/kg (1-39W pregnant)Reproductive: Specific developmental abnormalities: Craniofacial (including nose and tongue)

Reproductive: Specific developmental abnormalities: Musculoskeletal system
LANCAO 1,1415,1981
oral/woman 3276 mg/kg (1-39W pregnant)Reproductive: Maternal effects: Parturition

Reproductive: Effects on newborn: Stillbirth
POMDAS 62,64,1977
oral/woman 1092 mg/kg (1-91D pregnant)Reproductive: Effects on fertility: AbortionPOMDAS 62,64,1977
oral/rat 627 mg/kg (1-22D pregnant)Reproductive: Effects on newborn: Biochemical and metabolic

Reproductive: Effects on newborn: Other postnatal measures or effects
EXPEAM 36,1105,1980
oral/rat 85 mg/kg (3-19D pregnant)Reproductive: Effects on newborn: Behavioral

Reproductive: Effects on newborn: Physical
NTOTDY 8,29,1986
oral/rat 200 mg/kg (13-14D pregnant)Reproductive: Effects on embryo or fetus: Extra embryonic structures (e.g., placenta, umbilical cord)

Reproductive: Effects on embryo or fetus: Fetotoxicity (except death, e.g., stunted fetus)
TJADAB 26(3),8A,1982
oral/rat 1750 mg/kg (15-21D pregnant)Reproductive: Specific developmental abnormalities: Blood and lymphatic systems (including spleen and marrow)

Reproductive: Specific developmental abnormalities: Homeostasis
TXAPA9 22,449,1972
oral/rat 660 mg/kg (1-22D pregnant)Reproductive: Effects on fertility: Female fertility index (e.g., # females pregnant per # sperm positive females; # females pregnant per # females mated)

Reproductive: Specific developmental abnormalities: Urogenital system

Reproductive: Effects on newborn: Weaning or lactation index (e.g., # alive at weaning per # alive at day 4)
TXAPA9 44,1,1978
oral/rat 114 mg/kg (1-19D pregnant)Reproductive: Specific developmental abnormalities: Musculoskeletal systemFCHNA9 22(26),35,1980
oral/rat 120 mg/kg (12D pregnant)Reproductive: Effects on embryo or fetus: Maternal- fetal exchangeFAATDF 4,240,1984
oral/rat 150 mg/kg (2-11D pregnant)Reproductive: Other developmental abnormalitiesRFDEEH 11,211,1999
subcutaneous/mouse 200 mg/kg (12D pregnant)Reproductive: Effects on fertility: Post- implantation mortality (e.g., dead and/or resorbed implants per total number of implants)

Reproductive: Effects on embryo or fetus: Fetotoxicity (except death, e.g., stunted fetus)

Reproductive: Specific developmental abnormalities: Craniofacial (including nose and tongue)
JJPAAZ 19,134,1969
subcutaneous/mouse 150 mg/kg (13D pregnant)Reproductive: Specific developmental abnormalities: Craniofacial (including nose and tongue)

Reproductive: Specific developmental abnormalities: Musculoskeletal system

Reproductive: Other developmental abnormalities
TJADAB 12,79,1975
subcutaneous/mouse 150 mg/kg (13D pregnant)Reproductive: Effects on fertility: Post- implantation mortality (e.g., dead and/or resorbed implants per total number of implants)

Reproductive: Effects on fertility: Litter size (e.g., # fetuses per litter; measured before birth)
TJADAB 12,79,1975
subcutaneous/mouse 400 mg/kg (13D pregnant)Reproductive: Specific developmental abnormalities: Gastrointestinal systemFOMOAJ 29,316,1970
subcutaneous/rat 200 mg/kg (4D male)Reproductive: Effects on newborn: Viability index (e.g., # alive at day 4 per # born alive)PCBRD2 36,49,1980

Tumorigenic Data and References

Route/OrganismDoseEffectReference
oral/mouse lowest published toxic dose: 30800 mg/kg/44W- continuousTumorigenic: Carcinogenic by RTECS criteria

Skin and Appendages: Tumors

Tumorigenic: Increased incidence of tumors in susceptible strains
CNREA8 48,2078,1988
oral/rat lowest published toxic dose: 4200 mg/kg/10W- continuousTumorigenic: Neoplastic by RTECS criteria

Gastrointestinal: Colon tumors

Tumorigenic: Facilitates action of known carcinogens
CALEDQ 143,229,1999

Acute Toxicity Data and References

Route/OrganismDoseEffectReference
In Vitro/Chicken, neurons Inhibitor Concentration (50 percent kill): 39942 µmol/L/21HIn Vitro Toxicity Studies: Cell viability (mitochondrial reductase assays): MTT, XTT, MTS, WSTs assays etc.TIVIEQ 7,653,1993
In Vitro/Chicken, neurons Inhibitor Concentration (10 percent kill): 7604 µmol/L/21HIn Vitro Toxicity Studies: Cell viability (mitochondrial reductase assays): MTT, XTT, MTS, WSTs assays etc.TIVIEQ 7,653,1993
In Vitro/Chicken, neurons Inhibitor Concentration (50 percent kill): 39839 µmol/L/20HIn Vitro Toxicity Studies: Cell viability (lysosomal damage): neutral red assay etc.TIVIEQ 7,653,1993
In Vitro/Chicken, neurons Inhibitor Concentration (10 percent kill): 16546 µmol/L/20HIn Vitro Toxicity Studies: Cell viability (lysosomal damage): neutral red assay etc.TIVIEQ 7,653,1993
In Vitro/Human, endothelium Inhibitor Concentration (50 percent kill): 5 mmol/L/24HIn Vitro Toxicity Studies: Cell viability (lysosomal damage): neutral red assay etc.TIVIEQ 6,493,1992
In Vitro/Human, fibroblast Inhibitor Concentration (50 percent kill): 19 mmol/L/24HIn Vitro Toxicity Studies: Cell viability (lysosomal damage): neutral red assay etc.TIVIEQ 6,493,1992
In Vitro/Human, HeLa cell Inhibitor Concentration (50 percent kill): 1020 mg/L/24HIn Vitro Toxicity Studies: Cell membrane integrity: Cytoplasmic enzymes leakage (lactate dehydrogenase, ATP enzymes etc.)TIVIEQ 5,225,1991
In Vitro/Human, HeLa cell Inhibitor Concentration (50 percent kill): 1200 mg/L/24HIn Vitro Toxicity Studies: Cell proliferation: DNA incorporation, mitotic index etc.TIVIEQ 5,225,1991
In Vitro/Human, HeLa cell Inhibitor Concentration (50 percent kill): 800 mg/L/24HIn Vitro Toxicity Studies: Cell viability (mitochondrial reductase assays): MTT, XTT, MTS, WSTs assays etc.TIVIEQ 5,225,1991
In Vitro/Human, liver tumor Inhibitor Concentration (50 percent kill): 15 mmol/L/24HIn Vitro Toxicity Studies: Cell viability (lysosomal damage): neutral red assay etc.TIVIEQ 6,493,1992
In Vitro/Human, melanoma Inhibitor Concentration (50 percent kill): 12 mmol/L/24HIn Vitro Toxicity Studies: Cell viability (lysosomal damage): neutral red assay etc.TIVIEQ 6,493,1992
In Vitro/Human, neuroblastoma Inhibitor Concentration (20 percent kill): 92 µmol/L/30MIn Vitro Toxicity Studies: Other assaysTXAPA9 245,191,2010
In Vitro/Human, neuroblastoma Inhibitor Concentration (50 percent kill): 810 µmol/L/60MBiochemical: Enzyme inhibition, induction, or change in blood or tissue levels: True cholinesteraseTXAPA9 245,191,2010
In Vitro/Human, skin Inhibitor Concentration (50 percent kill): 18 mmol/L/24HIn Vitro Toxicity Studies: Cell viability (lysosomal damage): neutral red assay etc.TIVIEQ 6,493,1992
In Vitro/Mouse, fibroblast Inhibitor Concentration (10 percent kill): 550 µmol/L/24HIn Vitro Toxicity Studies: Cell viability (lysosomal damage): neutral red assay etc.TIVIEQ 2,1,1988
In Vitro/Mouse, fibroblast Inhibitor Concentration (50 percent kill): 3000 µmol/L/24HIn Vitro Toxicity Studies: Cell viability (lysosomal damage): neutral red assay etc.TIVIEQ 2,1,1988
In Vitro/Mouse, fibroblast Inhibitor Concentration (10 percent kill): 500 µmol/L/24HIn Vitro Toxicity Studies: Cell viability (mitochondrial reductase assays): MTT, XTT, MTS, WSTs assays etc.TIVIEQ 2,1,1988
In Vitro/Mouse, fibroblast Inhibitor Concentration (50 percent kill): 3500 µmol/L/24HIn Vitro Toxicity Studies: Cell viability (mitochondrial reductase assays): MTT, XTT, MTS, WSTs assays etc.TIVIEQ 2,1,1988
intracerebral/rat lowest published toxic dose: 66.7 µg/kgBehavioral: Change in motor activity (specific assay)PSCHDL 201,529,2009
intramuscular/infant lowest published toxic dose: 36 mg/kgBehavioral: Tremor

Behavioral: Ataxia
AJDCAI 134,495,1980
intramuscular/monkey lowest published toxic dose: 10 mg/kgBehavioral: AntipsychoticPSCHDL 200,393,2008
intramuscular/rabbit lowest published lethal dose: 200 mg/kgJPETAB 1,572,1910
intraperitoneal/cat lowest published lethal dose: 180 mg/kgHBAMAK 4,1335,1935
intraperitoneal/guinea pig lowest published lethal dose: 220 mg/kgHBAMAK 4,1335,1935
intraperitoneal/mouse lowest published toxic dose: 30 mg/kgBehavioral: Toxic psychosisEJPHAZ 499,147,2004
intraperitoneal/mouse lowest published toxic dose: 10 mg/kgBehavioral: AnalgesiaEJPHAZ 531,80,2006
intraperitoneal/mouse lethal dose (50 percent kill): 168 mg/kgBehavioral: Change in motor activity (specific assay)

Behavioral: Aggression

Kidney, Ureter, and Bladder: Urine volume increased
CPBTAL 22,1459,1974
intraperitoneal/mouse lowest published toxic dose: 3.5 mg/kgBehavioral: Change in motor activity (specific assay)PYTOEY 15,2,2008
intraperitoneal/mouse lowest published toxic dose: 20 mg/kgBehavioral: Change in motor activity (specific assay)

Behavioral: Alteration of classical conditioning
BJPCBM 154,471,2008
intraperitoneal/rabbit lowest published lethal dose: 150 mg/kgHBAMAK 4,1335,1935
intraperitoneal/rat lethal dose (50 percent kill): 240 mg/kgZERNAL 15,64,1976
intraperitoneal/rat lowest published toxic dose: 10 mg/kgBehavioral: Change in motor activity (specific assay)NEROEW 28,1281,2003
intraperitoneal/rat lowest published toxic dose: 0.3 mg/kgBehavioral: Change in psychophysiological testsBJMRDK 35,1201,2002
intraperitoneal/rat lowest published toxic dose: 60 mg/kgBehavioral: Convulsions or effect on seizure thresholdNRTXDN 33,127,2012
intravenous/cat lowest published toxic dose: 20 mg/kgVascular: Measurement of regional blood flowFATOAO 50,39,1987
intravenous/cat lowest published lethal dose: 80 mg/kgHBAMAK 4,1335,1935
intravenous/cattle lowest published toxic dose: 2.5 mg/kgGastrointestinal: Nausea or vomitingJAPTO* 21,229,2001
intravenous/Dog lowest published lethal dose: 4 mg/kgHBAMAK 4,1335,1935
intravenous/human lowest published toxic dose: 7 mg/kgBehavioral: Convulsions or effect on seizure thresholdAPTOA6 15,331,1959
intravenous/infant lowest published toxic dose: 68 mg/kgBehavioral: Somnolence (general depressed activity)

Behavioral: Tremor

Behavioral: Ataxia
AJDCAI 134,495,1980
intravenous/mouse lethal dose (50 percent kill): 62 mg/kgBehavioral: Convulsions or effect on seizure threshold

Lung, Thorax, or Respiration: Dyspnea
TOLED5 29,25,1985
intravenous/mouse lethal dose (50 percent kill): 62 mg/kgENTOX* ,706,2005
intravenous/rabbit lethal dose (50 percent kill): 58 mg/kgKSRNAM 13,791,1979
intravenous/rat lowest published toxic dose: 5 mg/kgBehavioral: Alteration of operant conditioningNEROEW 26,422,2002
intravenous/rat lowest published toxic dose: 0.5 mg/kgBiochemical: Neurotransmitters or modulators (putative): Dopamine at other sitesNEROEW 27,182,2002
intravenous/rat lethal dose (50 percent kill): 105 mg/kgLung, Thorax, or Respiration: Acute pulmonary edema

Kidney, Ureter, and Bladder: Structural or functional change in ureter
JPETAB 82,89,1944
intravenous/woman lowest published lethal dose: 57 mg/kgBehavioral: Convulsions or effect on seizure threshold

Vascular: BP elevation not characterized in autonomic section
APTOA6 15,331,1959
oral/cat lowest published lethal dose: 100 mg/kgHBAMAK 4,1335,1935
oral/child lowest published lethal dose: 320 mg/kgBehavioral: Convulsions or effect on seizure threshold

Lung, Thorax, or Respiration: Cyanosis
FNSCA6 3,275,1974
oral/child lowest published toxic dose: 140 mg/kgBehavioral: Muscle contraction or spasticity

Cardiac: Pulse rate increased without fall in BP

Blood: Hemorrhage
PECAE5 10,349,1994
oral/Dog lethal dose (50 percent kill): 140 mg/kgNIIRDN 6,174,1982
oral/guinea pig lethal dose (50 percent kill): 230 mg/kgBehavioral: Convulsions or effect on seizure threshold

Lung, Thorax, or Respiration: Respiratory depression
TXAPA9 2,23,1960
oral/hamster lethal dose (50 percent kill): 230 mg/kgGastrointestinal: Hypermotility, diarrheaTXAPA9 44,1,1978
oral/human lowest published toxic dose: 2.14 mg/kgBehavioral: Change in psychophysiological testsNEROEW 28,371,2003
oral/human lowest published toxic dose: 2 mg/kgBehavioral: Toxic psychosis

Vascular: BP elevation not characterized in autonomic section
PSCHDL 157,373,2001
oral/human lowest published toxic dose: 8.57 mg/kgBehavioral: Change in psychophysiological tests

Cardiac: Change in rate

Gastrointestinal: Nausea or vomiting
PSCHDL 159,238,2002
oral/human lowest published toxic dose: 1.5 mg/kgBehavioral: Antianxiety

Behavioral: Alteration of classical conditioning

Behavioral: Change in psychophysiological tests
JOPSEQ 19,620,2005
oral/human lowest published toxic dose: 5.71 mg/kgBrain and Coverings: Changes in surface EEGBJMRDK 38,1077,2005
oral/human lowest published toxic dose: 1.43 mg/kgBrain and Coverings: Recordings from specific areas of CNSNEROEW 29,1723,2004
oral/human lowest published lethal dose: 192 mg/kgJNDRAK 5,252,1965
oral/human lowest published toxic dose: 2.9 mg/kgNutritional and Gross Metabolic: Other changesCEXPB9 33,310,2006
oral/human lowest published toxic dose: 2.9 mg/kgBehavioral: Change in psychophysiological tests

Vascular: BP elevation not characterized in autonomic section
ECPPH* 16,13,2008
oral/infant lowest published toxic dose: 14700 µg/kgBehavioral: Muscle contraction or spasticityCLBIAS 10,148,1977
oral/man lowest published toxic dose: 51 mg/kgCardiac: Change in rate

Kidney, Ureter, and Bladder: Changes in tubules (including acute renal failure, acute tubular necrosis)

Musculoskeletal: Tumors
AEMED3 18,94,1989
oral/man lowest published toxic dose: 13 mg/kgBehavioral: Toxic psychosisAJPSAO 143,1320,1986
oral/man lowest published toxic dose: 2.86 mg/kgBrain and Coverings: Recordings from specific areas of CNS

Behavioral: Changes in REM sleep (human)
NEROEW 29,1933,2004
oral/man lowest published toxic dose: 1.5 mg/kgBehavioral: Change in psychophysiological testsJOPSEQ 17,283,2003
oral/man lowest published toxic dose: 2.143 mg/kgBehavioral: Altered sleep time (including change in righting reflex)PSCHDL 191,943,2007
oral/man lowest published toxic dose: 2.86 mg/kgBehavioral: Change in motor activity (specific assay)PSCHDL 202,719,2009
oral/monkey lowest published toxic dose: 30 mg/kgBehavioral: Change in motor activity (specific assay)

Behavioral: Alteration of classical conditioning
PSCHDL 197,59,2008
oral/monkey lowest published toxic dose: 30 mg/kgBehavioral: Change in motor activity (specific assay)PSCHDL 200,393,2008
oral/mouse lowest published toxic dose: 45 mg/kgKidney, Ureter, and Bladder: Urine volume increased

Kidney, Ureter, and Bladder: Other changes in urine composition

Nutritional and Gross Metabolic: Changes in: Na
JPETAB 313,403,2005
oral/mouse lethal dose (50 percent kill): 127 mg/kgGastrointestinal: Hypermotility, diarrheaTXAPA9 44,1,1978
oral/rabbit lethal dose (50 percent kill): 224 mg/kgGastrointestinal: Hypermotility, diarrheaTXAPA9 44,1,1978
oral/rat lethal dose (50 percent kill): 192 mg/kgBrain and Coverings: Other degenerative changes

Behavioral: Withdrawal

Kidney, Ureter, and Bladder: Interstitial nephritis
JNDRAK 5,252,1965
oral/rat lowest published toxic dose: 5 mg/kgBehavioral: Wakefulness

Behavioral: Altered sleep time (including change in righting reflex)
EJPHAZ 504,185,2004
oral/rat lowest published toxic dose: 5 mg/kgBehavioral: Alteration of operant conditioningPBBHAU 2,619,1974
oral/rat lowest published toxic dose: 5 mg/kgCardiac: Change in force of contraction

Nutritional and Gross Metabolic: Body temperature increase
FCTOD7 45,834,2007
oral/rat lowest published toxic dose: 15 mg/kgBehavioral: Wakefulness

Cardiac: Pulse rate increased without fall in BP

Vascular: BP elevation not characterized in autonomic section
FCTOD7 45,834,2007
oral/rat lowest published toxic dose: 45 mg/kgBehavioral: Somnolence (general depressed activity)

Vascular: BP lowering not characterized in autonomic section

Nutritional and Gross Metabolic: Body temperature decrease
FCTOD7 45,834,2007
oral/rat lowest published toxic dose: 10 mg/kgBehavioral: Altered sleep time (including change in righting reflex)PSCHDL 191,943,2007
oral/wild bird lethal dose (50 percent kill): 316 mg/kgAECTCV 12,355,1983
oral/woman lowest published toxic dose: 1000 mg/kgBehavioral: Convulsions or effect on seizure threshold

Cardiac: Arrythmias (indlucing changes in conduction)

Cardiac: Pulse rate increased without fall in BP
JTCTDW 41,1003,2003
oral/woman lowest published lethal dose: 400 mg/kgBehavioral: Convulsions or effect on seizure threshold

Cardiac: Other changes

Skin and Appendages: Other: Sweating
VHTODE 39,228,1997
oral/woman lowest published toxic dose: 96 mg/kg/1D- intermittentBehavioral: Hallucinations, distorted perceptions

Behavioral: Toxic psychosis

Gastrointestinal: Hypermotility, diarrhea
JOPDAB 105,493,1984
oral/woman lowest published lethal dose: 1 gm/kgGastrointestinal: Nausea or vomitingBIATDR -,6,1973
oral/woman lowest published toxic dose: 4 mg/kgBehavioral: Change in motor activity (specific assay)PSCHDL 202,719,2009
oral/woman lowest published toxic dose: 0.2 gm/kgCardiac: Arrythmias (indlucing changes in conduction)

Gastrointestinal: Nausea or vomiting

Nutritional and Gross Metabolic: Changes in: K
AJEMEN 27,253.e3,2009
parenteral/frog lowest published lethal dose: 120 mg/kgBehavioral: Convulsions or effect on seizure threshold

Behavioral: Stiffness

Cardiac: Other changes
AEPPAE 166,437,1932
rectal/rat lethal dose (50 percent kill): 300 mg/kgJCPHB8 7,131,1967
subcutaneous/cat lowest published lethal dose: 150 mg/kgHBAMAK 4,1335,1935
subcutaneous/Dog lethal dose (50 percent kill): 100 mg/kgNIIRDN 6,174,1982
subcutaneous/frog lowest published lethal dose: 120 mg/kgAPTOA6 15,331,1959
subcutaneous/guinea pig lowest published lethal dose: 200 mg/kgHBAMAK 4,1335,1935
subcutaneous/mouse lethal dose (50 percent kill): 242 mg/kgARZNAD 6,601,1956
subcutaneous/pigeon lowest published lethal dose: 140 mg/kgJPETAB 1,572,1910
subcutaneous/rabbit lowest published lethal dose: 275 mg/kgJPETAB 1,572,1910
subcutaneous/rat lethal dose (50 percent kill): 170 mg/kgJCPHB8 7,131,1967
subcutaneous/rat lowest published toxic dose: 194.2 µg/kgBiochemical: Metabolism (intermediary): Effect on inflammation or mediation of inflammationJPHSC* 100,310,2006
Tank with water/Zebrafish lowest published toxic concentration: 0.23 mmol/L 144HBlood: Other changes

Musculoskeletal: Other changes
REPTED 33,142,2012
Tank with water/Zebrafish lowest published toxic concentration: 0.23 mmol/L 144HSkin and Appendages: Other glandsREPTED 33,142,2012
Tank with water/Zebrafish lowest published toxic concentration: 3.79 mmol/L 24HRelated to Chronic Data: Death in the "MULTIPLE DOSE" data type fieldREPTED 33,142,2012
Tank with water/Zebrafish lowest published toxic concentration: 3.56 mmol/L 48HRelated to Chronic Data: Death in the "MULTIPLE DOSE" data type fieldREPTED 33,142,2012
Tank with water/Zebrafish lowest published toxic concentration: 3.48 mmol/L 72HRelated to Chronic Data: Death in the "MULTIPLE DOSE" data type fieldREPTED 33,142,2012
Tank with water/Zebrafish lowest published toxic concentration: 1.58 mmol/L 144HRelated to Chronic Data: Death in the "MULTIPLE DOSE" data type fieldREPTED 33,142,2012
unreported route/mouse lethal dose (50 percent kill): 251 mg/kgNYKZAU 53,2S,1957

Other Multiple Dose Data and References

Route/OrganismDoseEffectReference
intramuscular/mouse lowest published toxic dose: 13671 mg/kg/21W- continuousNutritional and Gross Metabolic: Weight loss or decreased weight gainNTIS** #PB85101202/AS
intramuscular/mouse lowest published toxic dose: 13671 mg/kg/21W- continuousLiver: Changes in liver weight

Reproductive: Paternal effects: Testes, epididymis, sperm duct

Reproductive: Paternal effects: Prostate, seminal vesicle, Cowper's gland, accessory glands
NTIS** #PB85101202/AS
intramuscular/mouse lowest published toxic dose: 1540 mg/kg/5W- continuousSkin and Appendages: Other: HairNTIS** #PB85101202/AS
intramuscular/rat lowest published toxic dose: 87.5 mg/kg/7D- intermittentNutritional and Gross Metabolic: Weight loss or decreased weight gainNTIS** #PB96-211743
intramuscular/rat lowest published toxic dose: 175 mg/kg/7D- intermittentBehavioral: Food intake (animal)NTIS** #PB96-211743
intramuscular/rat lowest published toxic dose: 87.5 mg/kg/7D- intermittentReproductive: Paternal effects: Spermatogenesis (including genetic material, sperm morphology, motility, and count)NTIS** #PB96-211743
intramuscular/rat lowest published toxic dose: 1750 mg/kg/20W- intermittentKidney, Ureter, and Bladder: Changes in kidney weightNTIS** #PB96-211743
intramuscular/rat lowest published toxic dose: 1750 mg/kg/20W- intermittentLiver: Changes in liver weightNTIS** #PB96-211743
intraperitoneal/mouse lowest published toxic dose: 300 mg/kg/17D- intermittentBehavioral: Change in psychophysiological testsPSCHDL 204,313,2009
intraperitoneal/mouse lowest published toxic dose: 30 mg/kg/3D- intermittentBehavioral: Alteration of operant conditioningPSCHDL 204,313,2009
intraperitoneal/rat lowest published toxic dose: 165 mg/kg/11D- intermittentBehavioral: Alteration of classical conditioningNETEEC 30,195,2008
intraperitoneal/rat lowest published toxic dose: 1050 mg/kg/21D- intermittentBehavioral: WithdrawalJOPSEQ 11,219,1997
oral/man lowest published toxic dose: 114.2 mg/kg/20D- intermittentBrain and Coverings: Changes in surface EEG

Vascular: Measurement of regional blood flow
PSCHDL 204,573,2009
oral/mouse lowest published toxic dose: 11200 mg/kg/20W- continuousBiochemical: Metabolism (intermediary): Effect on inflammation or mediation of inflammationCRNGDP 26,1965,2005
oral/mouse lowest published toxic dose: 19.7 gm/kg/32W- intermittentTumorigenic: Protects against induction of experimental tumorsCNREA8 66,11494,2006
oral/mouse lowest published toxic dose: 3500 mg/kg/5W- continuousTumorigenic: Active as anti-cancer agentCNREA8 67,651,2007
oral/mouse lowest published toxic dose: 9.66 mg/kg/15W- continuousBehavioral: Food intake (animal)

Behavioral: Change in motor activity (specific assay)

Biochemical: Metabolism (intermediary): Lipids including transport
LIFSAK 73,1383,2003
oral/rat lowest published toxic dose: 1689.8 mg/kg/14D- intermittentBehavioral: Change in motor activity (specific assay)

Behavioral: Tolerance
NEROEW 28,1281,2003
oral/rat lowest published toxic dose: 303.24 mg/kg/12W- continuousNutritional and Gross Metabolic: Weight loss or decreased weight gain

Tumorigenic: Active as anti-cancer agent
FCTOD7 39,541,2001
oral/rat lowest published toxic dose: 7280 mg/kg/52W- continuousTumorigenic: Protects against induction of experimental tumorsEMMUEG 39,271,2002
oral/rat lowest published toxic dose: 33210 mg/kg/90D- continuousGastrointestinal: Changes in structure or function of salivary glandsTOXID9 5,97,1985
oral/rat lowest published toxic dose: 380 mg/kg/4W- intermittentEndocrine: Changes in pituitary weight

Blood: Changes in other cell count (unspecified)
IJEBA6 22,298,1984
oral/rat lowest published toxic dose: 39900 mg/kg/19W- continuousNutritional and Gross Metabolic: Weight loss or decreased weight gain

Related to Chronic Data: Changes in testicular weight
JEPTDQ 2(3),687,1979
oral/rat lowest published toxic dose: 16800 mg/kg/8W- continuousBehavioral: Food intake (animal)

Endocrine: Changes in thymus weight

Related to Chronic Data: Changes in testicular weight
FCTOD7 22,365,1984
oral/rat lowest published toxic dose: 157 gm/kg/75W- continuousEndocrine: Changes in adrenal weight

Nutritional and Gross Metabolic: Weight loss or decreased weight gain

Related to Chronic Data: Changes in testicular weight
JEPTDQ 2(3),687,1979
oral/rat lowest published toxic dose: 490 mg/kg/7W- intermittentKidney, Ureter, and Bladder: Other changes

Kidney, Ureter, and Bladder: Changes in bladder weight
CYLPDN 27,1037,2006
oral/woman lowest published toxic dose: 160 mg/kg/20D- intermittentBrain and Coverings: Changes in surface EEG

Vascular: Measurement of regional blood flow
PSCHDL 204,573,2009
skin/mouse lowest published toxic dose: 2016 mg/kg/6W- intermittentBiochemical: Metabolism (intermediary): Effect on inflammation or mediation of inflammationCRNGDP 26,1965,2005
skin/mouse lowest published toxic dose: 12240 mg/kg/17W- intermittentTumorigenic: Protects against induction of experimental tumorsCRNGDP 28,199,2007
skin/mouse lowest published toxic dose: 2880 mg/kg/12W- intermittentTumorigenic: Protects against induction of experimental tumorsPNASA6 99,13455,2002
unreported route/rat lowest published toxic dose: 1000 mg/kg/10D- intermittentBehavioral: Alteration of classical conditioningNETEEC 32,503,2010

Reviews

OrganizationStandardReference
International Agency for Research on Cancer (IARC)Cancer Review:Human Inadequate EvidenceIMEMDT 51,291,1991
International Agency for Research on Cancer (IARC)Cancer Review:Animal Inadequate EvidenceIMEMDT 51,291,1991
International Agency for Research on Cancer (IARC)Cancer Review:Group 3IMEMDT 51,291,1991
TOXICOLOGY REVIEWFCTOD7 40,1271,2002
TOXICOLOGY REVIEWFCTOD7 40,1235,2002
TOXICOLOGY REVIEWFCTOD7 40,1243,2002
TOXICOLOGY REVIEWCLPTAT 5,480,1964
TOXICOLOGY REVIEW32XPAD -,49,1975
TOXICOLOGY REVIEWADVPA3 4,263,1966
TOXICOLOGY REVIEWFNSCA6 2,67,1973
TOXICOLOGY REVIEWFAATDF 13,747,1989
TOXICOLOGY REVIEWEPIRD7 14,83,1992
TOXICOLOGY REVIEWFCTOD7 40,9,2001
TOXICOLOGY REVIEWTOLED5 144,383,2003
TOXICOLOGY REVIEWTPHSDY 23,475,2002
TOXICOLOGY REVIEWTPHSDY 24,55,2003
TOXICOLOGY REVIEWECPPH* 6,87,1998
TOXICOLOGY REVIEWTPHSDY 24,139,2003
TOXICOLOGY REVIEWEMMUEG 45,271,2005
TOXICOLOGY REVIEWEMMUEG 44,163,2004
TOXICOLOGY REVIEWFSINDR 153,67,2005
TOXICOLOGY REVIEWPHTOEH 93,105,2003
TOXICOLOGY REVIEWNRTXDN 27,525,2006
TOXICOLOGY REVIEWBPCEM* 17,237,2003
TOXICOLOGY REVIEWEJPHAZ 545,51,2006
TOXICOLOGY REVIEWENTOX* -,377,2005
TOXICOLOGY REVIEWENTOX* -,742,2005
TOXICOLOGY REVIEWENTOX* -,69,2005
TOXICOLOGY REVIEWMUREAV 584,1,2005
TOXICOLOGY REVIEWNETEEC 29,425,2007
TOXICOLOGY REVIEWTOPADD 32(Suppl. 2),71,2004
TOXICOLOGY REVIEWHUTOX* -,259,1996
TOXICOLOGY REVIEWMUREAV 681,271,2009
TOXICOLOGY REVIEWCHMED* 3(12),-,2008
TOXICOLOGY REVIEWMUREAV 674,73,2009
TOXICOLOGY REVIEWPTPAD4 121,185,2009
TOXICOLOGY REVIEWMUREAV 667,82,2009
TOXICOLOGY REVIEWCPEMM* 9,35,2008
TOXICOLOGY REVIEWCEXPB9 33,838,2006
TOXICOLOGY REVIEWMUREAV 705,20,2010
TOXICOLOGY REVIEWNCLNA* 16,107,1998
TOXICOLOGY REVIEWNEUCL* 23,397,2005
TOXICOLOGY REVIEWNBREV* 5,1,1981
TOXICOLOGY REVIEWTXAPA9 243,239,2010
TOXICOLOGY REVIEWTXAPA9 243,134,2010
TOXICOLOGY REVIEWMUREAV 711,174,2011
TOXICOLOGY REVIEWREPTED 30,495,2010
TOXICOLOGY REVIEWNRTXDN 31,598,2010
TOXICOLOGY REVIEWMUREAV 721,27,2011
TOXICOLOGY REVIEWMUREAV 721,27,2011
TOXICOLOGY REVIEWMUREAV 750,1,2012
TOXICOLOGY REVIEWMUREAV 749,1,2012

Standards and Regulations

OrganizationStandardReference
Occupational Exposure Limit-RUSSIAshort term exposure limit 0.5 mg/m3, JUN2003

NIOSH Documentation and Surveillance

OrganizationStandardReference
National Occupational Exposure Survey 1983Hazard Code M1132; Number of Industries 19; Total Number of Facilities 1707; Number of Occupations 23; Total Number of Employees Exposed 19593; Total Number of Female Employees Exposed 11199
National Occupational Exposure Survey 1983Hazard Code X9210; Number of Industries 2; Total Number of Facilities 38; Number of Occupations 5; Total Number of Employees Exposed 373; Total Number of Female Employees Exposed 92
National Occupational Hazard Survey 1974Hazard Code M1132; Number of Industries 6; Total Number of Facilities 893; Number of Occupations 7; Total Number of Employees Exposed 5715

Status in Federal Agencies

OrganizationReference
EPA GENETOX PROGRAM 1988, Inconclusive: Cytogenetics-male germ cell
EPA GENETOX PROGRAM 1988, Inconclusive: In vitro SCE-human lymphocytes; In vivo SCE-nonhuman
EPA GENETOX PROGRAM 1988, Inconclusive: In vivo cytogenetics-nonhuman bone marrow
EPA GENETOX PROGRAM 1988, Inconclusive: Mouse spot test; B subtilis rec assay
EPA GENETOX PROGRAM 1988, Inconclusive: Rodent heritable translocation; Mammalian micronucleus
EPA GENETOX PROGRAM 1988, Negative/limited: Carcinogenicity-mouse/rat
EPA GENETOX PROGRAM 1988, Negative: Histidine reversion-Ames test; In vitro SCE-nonhuman
EPA GENETOX PROGRAM 1988, Negative: Mouse specific locus; Sperm morphology-mouse
EPA GENETOX PROGRAM 1988, Negative: SHE-clonal assay; Rodent dominant lethal
EPA GENETOX PROGRAM 1988, Negative: TRP reversion
EPA GENETOX PROGRAM 1988, Negative: UDS in mouse germ cells; V79 cell culture-gene mutation
EPA GENETOX PROGRAM 1988, Positive/dose response: In vitro cytogenetics-human lymphocyte
EPA GENETOX PROGRAM 1988, Positive: Cell transform.-SA7/SHE; In vitro cytogenetics-nonhuman
EPA GENETOX PROGRAM 1988, Positive: D melanogaster Sex-linked lethal; S cerevisiae-aneuploidy
EPA GENETOX PROGRAM 1988, Positive: D melanogaster-nondisjunction; N crassa-aneuploidy
EPA GENETOX PROGRAM 1988, Positive: D melanogaster-whole sex chrom. loss
EPA GENETOX PROGRAM 1988, Positive: E coli polA without S9; In vitro SCE-human
EPA TSCA Section 8(b) CHEMICAL INVENTORY
EPA TSCA Section 8(d) unpublished health/safety studies
EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001
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