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CHEM ISTRY D A T A B A S E
Compound Summary for CID 7577
4,4'-Methylenedianiline
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PubChem CID:
7577
Chemical Names:
4,4'-Methylenedianiline; 101-77-9; 4,4'-DIAMINODIPHENYLMETHANE; Dadpm; Methylenedianiline; Dianilinomethane More...
Molecular Formula:
C13 H14 N2 or NH2 C6 H4 CH2 C6 H4 NH2
Molecular Weight:
198.269 g/mol
InChI Key:
YBRVSVVVWCFQMG-UHFFFAOYSA-N
Substance Registry: Safety Summary:
FDA UNII Laboratory Chemical Safety Summary (LCSS)
4, 4'-methylenedianiline belongs to the family of Diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups[1]. Metabolite Description from Human Metabolome Database (HMDB) 4,4'-Methylenedianiline (MDA) is primarily used to produce 4,4'-methylenedianline diisocyanate and other polymeric isocyanates. Acute (short-term) oral and dermal exposure to MDA causes liver damage in humans and animals. MDA can irritate the skin and eyes in humans. No information is available on the chronic (long-term), reproductive, developmental, or carcinogenic effects of MDA in humans. In rats and mice exposed to the dihydrochloride salt of MDA in their drinking water, statistically significant increases in the incidence of several types of tumors, including liver and thyroid tumors, were reported. EPA has not classified MDA for carcinogenicity. The International Agency for Research on Cancer (IARC) has classified MDA as a Group 2B, possible human carcinogen. Hazards Summary from EPA Air Toxics 4,4'-DIAMINODIPHENYLMETHANE is a tan flake or lump solid with a faint fishlike odor. May be toxic by inhalation or ingestion, and may be irritating to skin. Insoluble in water. Physical Description from CAMEO Chemicals PUBCHEM
COMPOUND
4,4'-METHYLENEDIANILINE
Modify Date: 2018-04-07; Create Date: 2004-09-16
Contents 1 2D Structure 2 3D Conformer 3 Names and Identifiers 4 Chemical and Physical Properties 5 Related Records 6 Chemical Vendors 7 Food Additives and Ingredients 8 Pharmacology and Biochemistry 9 Use and Manufacturing 10 Identification 11 Safety and Hazards 12 Toxicity 13 Literature 14 Patents 15 Biological Test Results 16 Classification 17 Information Sources
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3 Names and Identifiers 3.1 Computed Descriptors 3.1.1 IUPAC Name 4-[(4-aminophenyl)methyl]aniline from PubChem
3.1.2 InChI InChI=1S/C13H14N2/c14-12-5-1-10(2-6-12)9-11-3-7-13(15)8-4-11/h1-8H,9,14-15H2 from PubChem
3.1.3 InChI Key YBRVSVVVWCFQMG-UHFFFAOYSA-N from PubChem
3.1.4 Canonical SMILES C1=CC(=CC=C1CC2=CC=C(C=C2)N)N from PubChem
3.2 Molecular Formula C13 H14 N2 from ILO-ICSC, PubChem NH2 C6 H4 CH2 C6 H4 NH2 from ILO-ICSC
3.3 Other Identifiers 3.3.1 CAS 101-77-9 from CAMEO Chemicals, ChemIDplus, DTP/NCI, EPA Chemicals under the TSCA, EPA DSStox, European Chemicals Agency - ECHA, Human Metabolome Database (HMDB), ILO-…
3.3.2 EC Number 202-974-4 from European Chemicals Agency - ECHA
3.3.3 ICSC Number 1111 from ILO-ICSC
3.3.4 NSC Number 4709 from DTP/NCI
3.3.5 RTECS Number BY5425000 from ILO-ICSC, The National Institute for Occupational Safety and Health - NIOSH
3.3.6 UN Number 2651 from CAMEO Chemicals, DOT Emergency Response Guidebook, ILO-ICSC, NJDOH RTK Hazardous Substance List
3.3.7 UNII GG5LL7OBZC from FDA/SPL Indexing Data
3.3.8 Wikipedia Title
4,4¢-methylenedianiline
Description
chemical compound from Wikipedia
3.4 Synonyms 3.4.1 MeSH Entry Terms 1. 4,4'-diaminodiphenylmethane 2. 4,4'-diaminodiphenylmethane dihydrochloride 3. 4,4'-diaminodiphenylmethane, sodium chloride (3:1) 4. 4,4'-MDA 5. 4,4'-methylene dianiline 6. 4,4'-methylenebisaniline 7. 4,4'-methylenedianiline 8. di(4-aminophenyl)methane 9. p,p'-diaminodiphenylmethane 10. Tonox from MeSH
3.4.2 Depositor-Supplied Synonyms 1. 4,4'-Methylenedianiline
11. 4-(4-Aminobenzyl)aniline
2. 101-77-9
21. Diaminodiphenylmethane
31. p,p'-Diaminodifenylmethan
41. 4,4'-Dimethylenediamine
12. Benzenamine, 4,4'-methylenebis- 22. Sumicure M
32. 4,4'-Methylenebisaniline
42. NSC 4709
3. 4,4'-DIAMINODIPHENYLMETHANE
13. p,p'-Diaminodiphenylmethane
23. Ancamine TL
33. 4,4'-Diaminodiphenylmethan
43. 4,4'-Methylenebis(aniline)
4. Dadpm
14. Bis(p-aminophenyl)methane
24. Di-(4-aminophenyl)methane
34. 4,4'-Methylenebisbenzenamine 44. Bis-p-aminofenylmethan [Czech]
5. Methylenedianiline
15. Epicure DDM
25. 4,4'-Methylenebis(benzeneamine) 35. Aniline, 4,4'-methylenedi-
45. CCRIS 1010
6. Dianilinomethane
16. Epikure DDM
26. Methylenebis(aniline)
36. Di(4-aminophenyl)methane
46. Methylenebis[aniline]
7. Tonox
17. Curithane
27. 4,4'-Methylene dianiline
37. Methylenedianiline (VAN)
47. CHEBI:32506
8. p,p'-Methylenedianiline
18. 4,4-Methylenedianiline
28. Bis-p-aminofenylmethan
38. NCI-C54604
48. Bis(aminophenyl)methane
9. Dianilinemethane
19. Jeffamine AP-20
29. Araldite hardener 972
39. Avaldite HT 972
49. HSDB 2541
20. 4,4'-Diphenylmethanediamine
30. 4-[(4-aminophenyl)methyl]aniline
40. HT 972
50. alpha-(p-aminophenyl)-p-toluidine
10. Bis(4-aminophenyl)methane
from PubChem
4 Chemical and Physical Properties 4.1 Computed Properties Property Name
Property Value
Molecular Weight
198.269 g/mol
Hydrogen Bond Donor Count
2
Hydrogen Bond Acceptor Count
2
Rotatable Bond Count
2
Complexity
157
CACTVS Substructure Key Fingerprint
AAADccBzAAAAAAAAAAAAAAAAAAAAAAAAAAAwYAAAAAAAAAABQAAAHAAQAAAAD AiBGAAwwIBAAACAAiRCQACCAAAgAgAIiAAAZIgIICKAkZGAIABgkAAIyAcQgMAOCAAAA AAAAAAQAAAAAAAAAAAAAAAAAA==
Topological Polar Surface Area
52 A^2
Monoisotopic Mass
198.116 g/mol
Exact Mass
198.116 g/mol
XLogP3
1.6
Compound Is Canonicalized
true
Formal Charge
0
Heavy Atom Count
15
Defined Atom Stereocenter Count
0
Undefined Atom Stereocenter Count
0
Defined Bond Stereocenter Count
0
Undefined Bond Stereocenter Count
0
Isotope Atom Count
0
Covalently-Bonded Unit Count
1 from PubChem
4.2 Experimental Properties 4.2.1 Physical Description 4,4'-DIAMINODIPHENYLMETHANE is a tan flake or lump solid with a faint fishlike odor. May be toxic by inhalation or ingestion, and may be irritating to skin. Insoluble in water. from CAMEO Chemicals 1. DryPowder 2. DryPowder, Liquid 3. Liquid 4. OtherSolid from EPA Chemicals under the TSCA Solid from Human Metabolome Database (HMDB) COLOURLESS-TO-PALE-YELLOW FLAKES WITH CHARACTERISTIC ODOUR. TURNS DARK ON EXPOSURE TO AIR.
from ILO-ICSC Pale-brown, crystalline solid with a faint, amine-like odor. from The National Institute for Occupational Safety and Health - NIOSH
4.2.2 Color Crystals from water or benzene O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 506
from HSDB Tan flakes, lumps, or pearly leaflets from benzene Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2436
from HSDB Plates or needles (water); plates (benzene) Lide, D.R. CRC Handbook of Chemistry and Physics 88TH Edition 2007-2008. CRC Press, Taylor & Francis, Boca Raton, FL 2007, p. 3-140
from HSDB Light-brown crystals Burdock, G.A. (ed.). Fenaroli's Handbook of Flavor Ingredients. 4th ed.Boca Raton, FL 2002, p. 385
from HSDB Light tan to white crystalline solid Amini B, Lowenkron S; Kirk-Othmer Encyclopedia of Chemical Technology. (2005). NY, NY: John Wiley & Sons; Aniline and Its Derivatives. Online Posting Date: July 18, 2003.
from HSDB
4.2.3 Odor Faint, amine-like odor Amini B, Lowenkron S; Kirk-Othmer Encyclopedia of Chemical Technology. (2005). NY, NY: John Wiley & Sons; Aniline and Its Derivatives. Online Posting Date: July 18, 2003.
from HSDB
4.2.4 Boiling Point 748 to 750° F at 768 mm Hg (NTP, 1992) from CAMEO Chemicals 398 deg C Lide, D.R. CRC Handbook of Chemistry and Physics 88TH Edition 2007-2008. CRC Press, Taylor & Francis, Boca Raton, FL 2007, p. 3-140
from HSDB at 102kPa: 398-399°C from ILO-ICSC 748°F from The National Institute for Occupational Safety and Health - NIOSH
4.2.5 Melting Point 197 to 198° F (NTP, 1992) from CAMEO Chemicals 92.5 deg C
Lide, D.R. CRC Handbook of Chemistry and Physics 88TH Edition 2007-2008. CRC Press, Taylor & Francis, Boca Raton, FL 2007, p. 3-140
from HSDB 92.5 °C from Human Metabolome Database (HMDB) 91.5-92°C from ILO-ICSC 198°F from The National Institute for Occupational Safety and Health - NIOSH
4.2.6 Flash Point 430° F (NTP, 1992) from CAMEO Chemicals 428 deg F (220 deg C) (closed cup) Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997., p. 325-68
from HSDB 220°C c.c. from ILO-ICSC 374°F from The National Institute for Occupational Safety and Health - NIOSH
4.2.7 Solubility less than 1 mg/mL at 66° F (NTP, 1992) from CAMEO Chemicals Slightly sol in cold water. Very sol in alcohol, benzene, ether O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 506
from HSDB Solubility (g/100mL solvent at 25 deg C): 273.0 in acetone; 9.0 in benzene; 0.7 in carbon tetrachloride; 9.5 in ethyl ether; 143.0 in methanol; 0.1 in water Amini B, Lowenkron S; Kirk-Othmer Encyclopedia of Chemical Technology. (2005). NY, NY: John Wiley & Sons; Aniline and Its Derivatives. Online Posting Date: July 18, 2003.
from HSDB In water, 1.00X10+3 mg/L at 25 deg C Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984., p. V2: 338
from HSDB 1 mg/mL at 25 °C from Human Metabolome Database (HMDB) in water: poor from ILO-ICSC 0.1% from The National Institute for Occupational Safety and Health - NIOSH
4.2.8 Density 1.15 at 77° F (NTP, 1992)
from CAMEO Chemicals 1.070 g/mL at 103 deg C Amini B, Lowenkron S; Kirk-Othmer Encyclopedia of Chemical Technology. (2005). NY, NY: John Wiley & Sons; Aniline and Its Derivatives. Online Posting Date: July 18, 2003.
from HSDB 0.5 g/cm³ from ILO-ICSC 1.06 (Liquid at 212°F) from The National Institute for Occupational Safety and Health - NIOSH
4.2.9 Vapor Density 6.8 (NTP, 1992) (Relative to Air) from CAMEO Chemicals 6.8 (Air = 1) IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php , p. V39: 348 (1986)
from HSDB
4.2.10 Vapor Pressure 1e-07 mm Hg at 77° F (calculated) (NTP, 1992) from CAMEO Chemicals 2.03X10-7 mm Hg at 25 deg C Amini B, Lowenkron S; Kirk-Othmer Encyclopedia of Chemical Technology. (2005). NY, NY: John Wiley & Sons; Aniline and Its Derivatives. Online Posting Date: July 18, 2003.
from HSDB Vapour pressure Pa at 197°C: 133 from ILO-ICSC (77°F): 0.0000002 mmHg from The National Institute for Occupational Safety and Health - NIOSH
4.2.11 LogP log Kow = 1.59 Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995.
from HSDB 1.59 from Human Metabolome Database (HMDB) 1.6 from ILO-ICSC
4.2.12 Stability OXIDIZES IN AIR; PALE YELLOW CRYSTALS TURN DARK COLOR WHEN EXPOSED TO AIR. IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume
work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php , p. V4 79 (1974)
from HSDB
4.2.13 Decomposition When heated to decomposition it emits highly toxic fumes of aniline and NOx. Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2437
from HSDB
4.2.14 Viscosity 8.3 cP at 100 deg C Amini B, Lowenkron S; Kirk-Othmer Encyclopedia of Chemical Technology. (2005). NY, NY: John Wiley & Sons; Aniline and Its Derivatives. Online Posting Date: July 18, 2003.
from HSDB
4.2.15 Heat of Vaporization 95.4 kJ/mol Amini B, Lowenkron S; Kirk-Othmer Encyclopedia of Chemical Technology. (2005). NY, NY: John Wiley & Sons; Aniline and Its Derivatives. Online Posting Date: July 18, 2003.
from HSDB
4.2.16 pH Weak base IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php , p. V4: 79 (1974)
from HSDB
4.2.17 Ionization Potential 10.70 eV from The National Institute for Occupational Safety and Health - NIOSH
4.3 Crystal Structures Crystal Structures: 1 of 1 (CCDC Number) CCDC Number
740258
Crystal Structure Data
DOI:10.5517/ccsv996
Associated Article
DOI:10.1039/b916368a from The Cambridge Structural Database
4.4 Spectral Properties SADTLER REFERENCE NUMBER: 7846 (IR, PRISM) Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979., p. C-372
from HSDB Intense mass spectral peaks: 198 m/z (100%), 106 m/z (33%), 182 m/z (19%), 199 m/z (14%) Hites, R.A. Handbook of Mass Spectra of Environmental Contaminants. Boca Raton, FL: CRC Press Inc., 1985., p. 195
from HSDB MASS: 29855 (NIST/EPA/MSDC Mass Spectral Database 1990 version) Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V1: 536
from HSDB IR: 6249 (Coblentz Society Spectral Collection) from HSDB UV: 18317 (Sadtler Research Laboratories Spectral Collection) Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V1: 536
from HSDB 1H NMR: 11592 (Sadtler Research Laboratories Spectral Collection) Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V1: 536
from HSDB
4.4.1 Infrared Spectra Infrared Spectra: 1 of 6 (FTIR Spectra) Technique
BETWEEN SALTS
Source of Sample
The Dow Chemical Company, Midland, Michigan
Copyright
Copyright © 1980, 1981-2018 Bio-Rad Laboratories, Inc. All Rights Reserved. LOADING... PLEASE WAIT...
Thumbnail
from SpectraBase Infrared Spectra: 2 of 6 (FTIR Spectra) Technique
MELT (LIQUID PHASE)
Source of Spectrum
SRL
Source of Sample
U.S. Rubber Company, Naugatuck Chemical Division, Naugatuck, Connecticut
Copyright
Copyright © 1980, 1981-2018 Bio-Rad Laboratories, Inc. All Rights Reserved. LOADING... PLEASE WAIT...
Thumbnail
from SpectraBase
Infrared Spectra: 3 of 6 (FTIR Spectra) Technique
KBr (4/1000)
Source of Spectrum
SCHOLL
Copyright
Copyright © 1980, 1981-2018 Bio-Rad Laboratories, Inc. All Rights Reserved. LOADING... PLEASE WAIT...
Thumbnail
from SpectraBase View All 6 Infrared Spectra
4.4.2 1D NMR Spectra 1D NMR Spectra: 1 of 4 (13C NMR Spectra) 13C NMR Spectra
1D NMR Spectrum 2764 - Varian 25.16 MHz 13C NMR from Human Metabolome Database (HMDB)
1D NMR Spectra: 2 of 4 (13C NMR Spectra) Copyright
Copyright © 2016 W. Robien, Inst. of Org. Chem., Univ. of Vienna. All Rights Reserved. LOADING... PLEASE WAIT...
Thumbnail
from SpectraBase 1D NMR Spectra: 3 of 4 (13C NMR Spectra) Source of Sample
Chem Service, Inc., West Chester, Pennsylvania
Copyright
Copyright © 1980, 1981-2018 Bio-Rad Laboratories, Inc. All Rights Reserved. LOADING... PLEASE WAIT...
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from SpectraBase View All 4 1D NMR Spectra
4.4.3 Mass Spectrometry 4.4.3.1 GC-MS GC-MS Spectrum 19572 - GC-MS Ei Predicted by CFMID-EI, energy0 from Human Metabolome Database (HMDB)
1 of 4 NIST Number
228923
Library
Main library
Total Peaks
115
m/z Top Peak
198
m/z 2nd Highest
197
m/z 3rd Highest
106 LOADING... PLEASE WAIT...
Thumbnail
from NIST
4.4.3.2 MS-MS 1. MS-MS Spectrum 77352 - 10V Positive Predicted by CFM-ID 2. MS-MS Spectrum 77353 - 20V Positive Predicted by CFM-ID 3. MS-MS Spectrum 77354 - 40V Positive Predicted by CFM-ID 4. MS-MS Spectrum 137451 - 10V Negative Predicted by CFM-ID 5. MS-MS Spectrum 137452 - 20V Negative Predicted by CFM-ID 6. MS-MS Spectrum 137453 - 40V Negative Predicted by CFM-ID from Human Metabolome Database (HMDB)
4.4.3.3 EI-MS EI-MS Spectrum 312 from Human Metabolome Database (HMDB)
5 Related Records LOADING... PLEASE WAIT...
from NCBI
5.1 Related Compounds with Annotation LOADING... PLEASE WAIT...
from PubChem
5.2 Related Compounds Same Connectivity
5 records
Same Parent, Connectivity
35 records
Same Parent, Exact
31 records
Mixtures, Components, and Neutralized Forms
98 records
Similar Compounds
2735 records
Similar Conformers
4363 records from PubChem
5.3 Substances 5.3.1 Related Substances All
393 records
Same
125 records
Mixture
268 records from PubChem
5.3.2 Substances by Category LOADING... PLEASE WAIT...
from PubChem
5.4 Entrez Crosslinks PubMed
133 records
Taxonomy
3 records
OMIM
12 records
Gene
3213 records from PubChem
6 Chemical Vendors LOADING... PLEASE WAIT...
from PubChem
7 Food Additives and Ingredients 7.1 FDA Indirect Additives used in Food Contact Substances FDA Indirect Additives used in Food Contact Substances: 1 of 1 (Indirect Additives) Indirect Additives
4,4'-METHYLENEDIANILINE
Title 21 of the U.S. Code of Federal Regulations (21 CFR)
Title 21 of the U.S. Code of Federal Regulations (21 CFR) 175.300; 177.1680; 177.2280; 177.2450; 177.2600; 177.2800 from FDA Center for Food Safety and Applied Nutrition (CFSAN)
8 Pharmacology and Biochemistry 8.1 MeSH Pharmacological Classification Carcinogens Substances that increase the risk of NEOPLASMS in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included. See a list of PubChem compounds matching this category. from MeSH
8.2 Absorption, Distribution and Excretion ... Male rats, guinea pigs and monkeys /were/ treated topically with a low (2 mg/kg bw) or high (20 mg/kg bw) dose of 14C-MDA. In rats, 43% and 10% of the low dose was recovered in urine and feces during a 96 hours period; 2% remained in tissues and skin washing removed 25% of dose. The remainder (26%) was recovered by skin extraction and solubilisation. The percentage of dose absorbed decreased by increasing the dose, but the total amount absorbed (approx. 0.225 mg/rat) was similar after both doses. In guinea pigs, 10% and 18% of the low dose was excreted in urine and feces; 1% was recovered in tissue, 41% in the skin wash and 29% from the application area. The percent of dose absorbed decreased following the high dose, but the amounts absorbed (in mg/animal) doubled. Organization for Economic Cooperation and Development; Screening Information Data Set for 4,4'-Methylenedianiline, CAS# 101-77-9 p.146. Available from, as of February 27, 2009: http://www.chem.unep.ch/irptc/sids/OECDSIDS/sidspub.html
from HSDB ... The percutaneous absorption of MDA /was invesitgated using/ ... full-thickness rat and human skin in vitro. In this study MDA was topically applied (17.7 - 40.6 ug/sq cm in ethanol) to unoccluded skin, using a flow-through diffusion cell. After 72 hours the absorption into the receptor fluid reached 6.1 +/- 2.0% for rat skin and 13.0 +/- 4.3% for human skin related to applied dose. When the skin was occluded, the absorption of MDA was significantly enhanced reaching approx. 13.3% and 33% for rat and human skin, respectively. At the end of each experiment, considerable residual material remained with the skin (about 23-58%). Organization for Economic Cooperation and Development; Screening Information Data Set for 4,4'-Methylenedianiline, CAS# 101-77-9 p.145. Available from, as of February 27, 2009: http://www.chem.unep.ch/irptc/sids/OECDSIDS/sidspub.html
from HSDB MDA is absorbed via skin as well as from the gastrointestinal tract. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB The disposition of MDA was also examined following iv administration. In rats, 67% and 31% of the low dose (2 mg/kg bw) was recovered in urine and feces by 96 hr after dosing. In monkeys, the radioactivity occurred primarily in the urine (85%) by 168 hr after dosing (2 mg/kg bw). In guinea pigs, however, 35% and 57% of the dose were eliminated in urine and feces, respectively, during 96 hours. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB ... The in vivo mass balance of (14)C-MDA /was studied/ in rats and rabbits given a single ip dose of the compound. Four male rats, and a male rabbit of each acetylator phenotype were administered 30 mg/kg and 50 mg/kg of (14)C-MDA, respectively. The excretion of radioactivity into the urine and feces was followed daily for 4 days. Since the compound was administered by the intraperitoneal route, the amount of fecal radioactivity provided an indication of biliary excretion. The results show that both species excrete a majority of the radioactivity within two days. In the rat, the main route of excretion is the feces (55.8%) compared to urine (35.0%); whereas the rabbit, regardless of phenotype, excretes about 80% of the radiolabel in the urine. The total recovery of radioactivity from the rat and slow acetylator rabbit is about 10% less than the recovery from the fast acetylator rabbit. This difference in recovery between fast and slow acetylating rabbits is associated with the greater fecal excretion by the fast acetylator rabbit. The residual radioactivity in the organs tends to localize in the liver, kidney, spleen and thyroid at both 24 and 96 hours. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB Renal excretion of MDA and its metabolites dominates in rats (after i.v. administration) and monkeys and rabbits. However, after i.p. administration of MDA reported for rats the excretion via the feces as main way. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB A single dose of (14)C-ring labeled 4,4'-methylenedianiline (2 or 20 mg/kg) in ethanol/water was applied to the back of rats and the area was covered with a cup. After an exposure of 6 hours, a total of approximately 12% of the applied radioactivity was recovered in the urine, feces, gastrointestinal tract and tissues; 62% was recovered in a wash with soap and water, and 30% remained in the application site (total recoveries from radiotracer studies often exceed 100%). A 24-hour exposure period resulted in a combined 27% of the dose in urine, feces, gastrointestinal tract and
tissues, 52% in the wash, and 25% in the application site. After a 96-hour exposure period, 55% of the dose was accounted for by the combined urine, feces, gastrointestinal tract, and tissues, 25% was in the wash and 26% in the application site. The results also showed that after washing, test material which remained within the skin continued to be absorbed. Moreover, occlusion facilitated absorption. When two dose levels were tested, the amount of radioactivity in tissues was higher after the high dose, but the proportion of the applied dose was lower than with the low dose, which suggested a dose-dependent absorption rate. Finally, a greater percentage of the dose was absorbed when the application site was washed with acetone and water 5 minutes after dosing than when washed with soap and water. DHHS/ATSDR; Toxicological Profile for Methylenedianiline (PB/99/102568/AS) (August 1998). Available from, as of February 23, 2009: http://www.atsdr.cdc.gov/toxpro2.html#bookmark05
from HSDB The distribution of 4,4'-methylenedianiline (or metabolites) has also been studied in rats and guinea pigs after a single intravenous injection. Rats were injected (14)C-ring-labeled 4,4'methylenedianiline (2 mg/kg) in ethanol water and sacrifices were conducted 6, 24, or 96 after dosing. After 6 hours, the gastrointestinal tract had the highest amount of radioactivity (24% of the dose); this was followed by the liver (9.5%), skin (3.2%), and blood (2.8%). Twenty-four hours after the injection, the amount of radioactivity had decreased considerably in all tissues, and the liver and gastrointestinal tract had about 4% of the administered dose. Ninety-six hours after dosing, the liver had 4 or more times higher radioactivity (0.9%) than any other tissue. On a per gram basis, the liver had the highest concentration of radioactivity at all times, followed by the lungs at 6 and 24 hours and the spleen at 96 hours. Except for the liver, no preferential accumulation was apparent. The guinea pigs were treated the same as the rats except that sacrifices were conducted only 96 hours after the injection. As a percentage of the applied dose, the liver had the most radioactivity, about 3 times that found in blood. On a per gram basis, radioactivity was most concentrated in the spleen, followed by the liver, and preferential accumulation in these organs was suggested. Total recovery as a percentage of the dose, in blood, tissues, and gastrointestinal tract was 0.55%, 2.4% and 0.61%, respectively. DHHS/ATSDR; Toxicological Profile for Methylenedianiline (PB/99/102568/AS) (August 1998). Available from, as of February 23, 2009: http://www.atsdr.cdc.gov/toxpro2.html#bookmark05
from HSDB In monkeys, most of the dose (79%) was excreted in the urine within the first 48 hours; at this time 6.5% of the dose appeared in the feces. Total recovery of radioactivity over a the 168-hour collection period amounted to 94% of the injected dose. As seen in rats, urine was the main route of excretion in monkeys. DHHS/ATSDR; Toxicological Profile for Methylenedianiline (PB/99/102568/AS) (August 1998). Available from, as of February 23, 2009: http://www.atsdr.cdc.gov/toxpro2.html#bookmark05
from HSDB In order to estimate human exposure it is useful to determine percutaneous penetration. Previous studies have suggested that both rat and human skin were permeable to MDA, with greater penetration being seen through human skin. In this study no significant difference was seen between the percutaneous penetration of MDA through human or rat skin for three different treatment levels: 0.01, 0.1 and 1mg per skin membrane (0.32 sq cm). The apparent dermal flux was calculated as 0.7 +/- 0.3 and 10.1 +/- 2.0 ug/sq cm/hr for the 0.01 and 0.1 mg treatments, respectively. The permeability constant K(p) was estimated at 1.8 x 10(-3) cm/hr and the lag time at 3.5 +/- 0.5 hr. MDA absorbed into the skin was found to be bioavailable. Experiments also showed that after application of 0.1 mg MDA, 4% penetrated through latex and nitrile gloves, respectively. The potential genotoxicity of MDA in human skin was assessed by DNA (32)P-postlabelling; levels of DNA adducts were detected, following the treatment and penetration of 1mg MDA. Abstract: PubMed Kenyon, SH et al; Toxicology 196 (1-2): 65-75 (2004)
from HSDB ...Gender affected the disposition of 4,4'-diaminodiphenylmethane (DAPM) metabolites. At 25 mg DAPM/ kg, male rats had greater amounts of DAPM/metabolite in bile and liver, while females had greater amounts in serum and urine. ... Abstract: PubMed Dugas, TR et al; Journal of Toxicology and Environmental Health. Part A 62 (6): 467-483 (2001)
from HSDB Five healthy volunteers /were exposed/ dermally for 1 hr to 0.75-2.25 umol MDA dissolved in isopropanol, by use of a patch-test technique. Determination of MDA remaining in the patch units after exposure showed that a median of 28% (range 25-29%) was absorbed. After hydrolyzing MDA has been determined in plasma with an initial peak and a decline after removing the patch. MDA was also detected in hydrolyzed urine. The maximum rate of MDA excretion in urine was found 6-11 hours after the onset of exposure. Within two subjects studied at three doses, the urinary excretion was proportional to the exposure. The elimination half-lives in plasma and urine had medians at 13 and 7 hours, respectively. In eight out of nine exposures, the elimination halflife was longer in plasma than in urine. Slow acetylation seemed to be associated with short elimination half-life in urine. The median of total MDA amount excreted in urine during 48 hours, was 33 nmol for the five subjects exposed to 0.75 umol, which corresponds to roughly 16% (range 2%-26%) of the absorbed dose. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB Excretion of metabolites occurs fastest when exposure is via inhalation, dermal absorption will result in slower excretion. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB ... Given as an ip injection in propylene glycol at a dose of 5 mg DAPM/kg body wt, about 25% appears in the bile within 24 hr in the form of 3 or 4 unidentified metabolites. IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php , p. V4 83 (1974)
from HSDB
8.3 Metabolism/Metabolites
A sensitive and specific gas chromatographic/mass spectrometric assay is described for the determination of N-acetyl 4,4'-methylene dianiline and N-acetyl 4,4'-methylene-bis(2-chloroaniline) in urine. The method is based on the solvent extraction of the compounds together with deuterium-labeled internal standards, the compounds being separated and detected by capillary gas chromatography/mass spectrometry as their pentafluoropropyl derivatives. The method has been applied to the detection of 4,4'-methylene-bis(2-chloroaniline) and N-acetyl 4,4'-methylene dianiline in the the urine of workers occupationally exposed to 4,4'-methylene-bis(2-chloroaniline) and 4,4'-methylenedianiline. The results show that while N-acetyl 4,4'-methylene-bis(2chloroaniline) is a relatively minor urinary metabolite a significant proportion of 4,4'-methylenedianiline is excreted as the N-acetylated compound. Cocker J et al; Biomed Environ Mass Spectrum 17 (3): 161-7 (1988)
from HSDB Monoacetyl-4,4'- methylenebis-(2-chloraniline) and monoacetyl-4,4'-methylenedianiline were found in urine of workers exposed to 4,4'-methylenebis-(2-chloraniline) and 4,4'-methylenedianiline. Urine samples collected at the end of a shift showed that the concentration of monoacetyl-4,4'-methylenebis-(2-chloroaniline) was less than 5 percent that of 4,4'-methylenebis-(2-chloroaniline); however, urinary concentration of monoacetyl-4,4'-methylenedianiline was between 20 and 160 percent that of 4,4'-methylenedianiline. It was concluded that acetylation reduces the mutagenicity of 4,4'-methylenebis-(2-chloroaniline) and 4,4'-methylenedianiline. Cocker J et al; Food Chem Toxicol 24 (6/7): 755-6 (1986)
from HSDB Upon a single i.p. administration of MDA to Sprague-Dawley rats (30 mg/kg bw) at least 17 urinary metabolites were found. Mainly, the following acetylated metabolites have been identified: Nacetyl-MDA, N,N-diacetyl-MDA, N,N-diacetyl-3-hydroxy-MDA, N-acetyl-4,4'-diaminobenzophenone, and N,N-diacetyl-4,4'-diamino-benzhydrol. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /Researchers/ investigated the formation of stable urinary metabolites in post-shift urine from 63 workers exposed to MIDA. MDA, N-acetyl-MDA (MAMIDA) and N,N'-diacetyl-MDA (DAMDA) were determined in non-hydrolyzed urine samples, and that of total MDA on urine samples after alkaline hydrolysis. Their relative concentrations (arithmetic means) were found to be in the following order: total MDA /greater than/ MAMDA /greater than/ MDA /greater than/ DAMDA. While MAMDA represented more than 50% of total MDA, MDA and DAMDA were lower than 15% and 3% respectively. Acetylation of MDA, described as a possible way of detoxification, is confirmed to be an important metabolism route in humans, essentially through the monoacetylated metabolite. However, the individual ratio MAMDA/total MDA was found to vary widely (roughly from 0% to 100%). The half-life was found to be between 9 and 14 hours. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB Based on data from structurally-related compounds and from a study with 4,4'-methylenedianiline in vitro, it seems that metabolism of 4,4'-methylenedianiline occurs in the liver. N-hydroxylation leads to N-hydroxylamine, a potentially toxic intermediate that can bind to macromolecule, or can be deactivated by conjugation with glutathione. DHHS/ATSDR; Toxicological Profile for Methylenedianiline (PB/99/102568/AS) (August 1998). Available from, as of February 23, 2009: http://www.atsdr.cdc.gov/toxpro2.html#bookmark05
from HSDB In vitro metabolism of MDA was investigated using rabbit liver microsomes. The following three metabolites were detected: azo-MDA, azoxy-MDA, and nitroso-MDA (4- nitroso-4'aminodiphenylmethane). The azo and azoxy compounds were produced enzymatically, whereas the nitroso compound may have been formed via a non-enzymatic process. The hydroxylamine of MDA could not been detected in this study. However, its initial formation has to be supposed as prerequisite for the formation of the dimeric MDA metabolites azo- and azoxy- MDA Organization for Economic Cooperation and Development; Screening Information Data Set for 4,4'-Methylenedianiline, CAS# 101-77-9 p.147. Available from, as of February 27, 2009: http://www.chem.unep.ch/irptc/sids/OECDSIDS/sidspub.html
from HSDB ...MDA undergoes N-acetylation catalyzed by N-acetyltransferase 1 (NAT1) and 2 (NAT2) in the liver. Both human and rat NAT2 are polymorphic, and human NAT2 genetic polymorphism modifies the frequency and/or severity of drug and xenobiotic toxicity in human populations. ... Abstract: PubMed Zhang, X et al; The Journal of Pharmacology and Experimental Therapeutics 316 (1): 289-294 (2006)
from HSDB ... In the present study it was investigated whether the formation of Hb adducts from non-nitroso metabolites of MDA can be used for the dosimetry of MDA. The study was carried out by treatment of mice with MDA and tritiated MDA or deuterated MDA and by identification of their products of reaction with Hb, after enzymatic hydrolysis of the globin and enrichment of the adducts. The main adduct, about 50% of the total amount of MDA associated with Hb, was characterized by MS and was shown to be a reaction product of MDA and the amino group of Nterminal valine in Hb, the derived structure being 1-[(4-imino-2, 5-cyclohexadien-1-ylidene)methyl]benzene-4-azo-2-isovaleric acid. It is likely that this quinonoid MDA imine adduct to valine was formed by an attack of a metabolite formed through peroxidative oxidation of MDA, in analogy with earlier observed oxidation of some other aromatic amines, eg, benzidine. The reactive intermediate is suggested to be [(4-imino-2, 5-cyclohexadien-1-ylidene)methyl]-4-aminobenzene. The formation of the adduct was confirmed by incubating MDA with valine methyl ester in vitro in the presence of H2O2 and lactoperoxidase. Further, the same adduct was detected in MDI-exposed and control rats, the level in the exposed animals being about 60 times higher than in the controls. This study indicates that, at least in the mouse, extrahepatic peroxidative metabolism is an important pathway for the bioactivation of MDA, possibly leading to a genotoxic reactive intermediate... Abstract: PubMed Kautiainen, A et al; Chemical Research in Toxicology 11 (6): 614-621 (1998)
from HSDB Although differences in the quantitative aspects of metabolism remains unelucidated, the in vivo biotransformation pathways of MDA involve N-acetylation reactions as well as an oxidation of the central C-atom and conjugation to glucuronides and sulfates.
European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB ... /The/ objective /of this study/ was to isolate, characterize, and quantify DAPM metabolites excreted into bile in both male and female bile duct-cannulated Sprague Dawley rats. The rats were gavaged with [(14)C]-DAPM, and the collected bile was subjected to reversed-phase HPLC with radioisotope detection. Peaks eluting from HPLC were collected and analyzed using electrospray MS and NMR spectroscopy. HPLC analysis indicated numerous metabolites in both sexes, but male rats excreted greater amounts of glutathione and glucuronide conjugates than females. Electrospray MS and NMR spectra of HPLC fractions revealed that the most prominent metabolite found in bile of both sexes was a glutathione conjugate of an imine metabolite of a 4'-nitrosoDAPM. Seven other metabolites were identified, including acetylated, cysteinyl-glycine, glutamyl-cysteine, glycine, and glucuronide conjugates. While ... prior studies demonstrated increased covalent binding of DAPM in the liver and bile of female compared to male rats, in these studies, SDS-PAGE with autoradiography revealed 4-5 radiolabeled protein bands in the bile of rats treated with [(14)C]-DAPM. In addition, these bands were much more prominent in female than in male rats. ...[Chen, K et al; Toxicol Appl Pharmacol 232 (2): 190-202 (2008)] Full text: PMC2614345 Abstract: PubMed from HSDB
8.4 Biological Half-Life About 13% of 33 mg MDA (0.5% in petrolatum) applied for 48 hours onto the back skin during patch testing were recovered in the urine within 57 hours. With the work-up procedure of the urine samples MDA and acetylated MDA could be detected. The biological half-time of excretion of these metabolites in urine can be estimated from levels in end-of-shift and next morning pre-shift urine samples to be between 9 and 14 hours. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB
8.5 Human Metabolite Information 8.5.1 Metabolite Description 4, 4'-methylenedianiline belongs to the family of Diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups[1]. from Human Metabolome Database (HMDB)
9 Use and Manufacturing 9.1 Uses Chemical Classification Benzidines/Aromatic amines from CDC-ATSDR Toxic Substances Portal MDA is primarily used to produce 4,4-'methylenedianiline diisocyanate and other polymeric isocyanates which are used to manufacture polyurethane foams. MDA is also used as a curing agent for epoxy resins and urethane elastomers, as a corrosion preventative for iron, as an antioxidant for lubricating oils, as a rubber processing chemical, as an intermediate in the manufacture of elastomeric fibers (e.g., Spandex), and in the preparation of azo dyes. from EPA Air Toxics
9.1.1 Industry Uses 1. CBI 2. Intermediates 3. Process regulators from EPA Chemicals under the TSCA
9.1.2 Consumer Uses CBI from EPA Chemicals under the TSCA
9.2 Methods of Manufacturing ... From aniline and formaldehyde; ... By hydrogenolysis of p,p'-diaminobenzophenone with LiAlH4. O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 506
from HSDB Acid-catalyzed reaction of formaldehyde with aniline; distillation from polymeric 4,4'-diaminodiphenylmethane. Amini B, Lowenkron S; Kirk-Othmer Encyclopedia of Chemical Technology. (2005). NY, NY: John Wiley & Sons; Aniline and Its Derivatives. Online Posting Date: July 18, 2003.
from HSDB
9.3 Impurities 2,4-diaminodiphenylmethane isomer, up to 3% Amini B, Lowenkron S; Kirk-Othmer Encyclopedia of Chemical Technology. (2005). NY, NY: John Wiley & Sons; Aniline and Its Derivatives. Online Posting Date: July 18, 2003.
from HSDB
9.4 Formulations/Preparations With a diamine assay of 98-99% Amini B, Lowenkron S; Kirk-Othmer Encyclopedia of Chemical Technology. (2005). NY, NY: John Wiley & Sons; Aniline and Its Derivatives. Online Posting Date: July 18, 2003.
from HSDB Sold in flaked or granular form Amini B, Lowenkron S; Kirk-Othmer Encyclopedia of Chemical Technology. (2005). NY, NY: John Wiley & Sons; Aniline and Its Derivatives. Online Posting Date: July 18, 2003.
from HSDB
9.5 U.S. Production (1972 SALES) 8.57X10+8 G SRI
from HSDB (1975) 4.10X10+8 G (SALES) SRI
from HSDB Benzenamine, 4,4'-methylenebis- is listed as a High Production Volume (HPV) chemical (65FR81686). Chemicals listed as HPV were produced in or imported into the U.S. in >1 million pounds in 1990 and/or 1994. The HPV list is based on the 1990 Inventory Update Rule. (IUR) (40 CFR part 710 subpart B; 51FR21438). EPA/Office of Pollution Prevention and Toxics; High Production Volume (HPV) Challenge Program. Available from the Database Query page at: http://www.epa.gov/hpv/pubs/general/opptsrch.htm on Benzenamine, 4,4'-methylenebis- (101-77-9) as of February 18, 2009
from HSDB Production volumes for non-confidential chemicals reported under the Inventory Update Rule. Year
Production Range (pounds)
1986
>100 million - 500 million
1990
>1 million - 10 million
1994
>1 million - 10 million
1998
>1 million - 10 million
2002
>1 million - 10 million
US EPA; Non-confidential Production Volume Information Submitted by Companies for Chemicals Under the 1986-2002 Inventory Update Rule (IUR). Benzenamine, 4,4'-methylenebis- (101-77-9). Available from, as of February 18, 2009: http://www.epa.gov/oppt/iur/tools/data/2002-vol.html
from HSDB
9.6 U.S. Imports (1972) 1.6X10+6 G SRI
from HSDB (1974) 1.00X10+6 G SRI
from HSDB
9.7 Sampling Procedures NIOSH Method 5029. Analyte: 4,4'-methylenedianiline. Matrix: Air. Sampler: Filter (acid-treated glass fibers, 37 mm). Flow Rate: 1 to 2 l/min. Sample Size: 100 liters. Shipment: Transfer filter to glass vial; extract with 4 ml 0.1 N methanolic potassium hydroxide before shipping. Sample Stability: Stable at least 60 days at 20 deg C. U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984., p. 5029-1
from HSDB
10 Identification 10.1 Analytic Laboratory Methods GUIDELINES FOR ANALYSIS OF AROMATIC AMINES ARE AVAILABLE. THE GAS CHROMATOGRAPHIC IDENTIFICATION IS ALSO AVAILABLE. IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php , p. V4 82 (1974)
from HSDB Method: NIOSH 5029, Issue 2; Procedure: high performance liquid chromatography with ultraviolet and electrochemical detection; Analyte: 4,4'-methylenedianiline; Matrix: air; Detection Limit: ultraviolet detection 0.12 ug per sample; electrochemical detection 0.007 ug per sample. CDC; NIOSH Manual of Analytical Methods, 4th ed. 4,4'-Methylenedianiline (101-77-9). Available from, as of February 19, 2009: http://www.cdc.gov/niosh/docs/2003-154/
from HSDB Method: OSHA 57; Procedure: gas chromatography using an electron capture detector; Analyte: 4.4'-methylenedianiline; Matrix: air; Detection Limit: 10 parts per trillion (81 nanogram/cu m) . U.S. Department of Labor/Occupational Safety and Health Administration's Index of Sampling and Analytical Methods. Available from: http://www.osha.gov/dts/sltc/methods/toc.html on 4,4'Methylenedianiline (101-77-9) as of February 19, 2009
from HSDB
10.2 OSHA Chemical Sampling 4,4'-Methylenedianiline from OSHA Chemical Sampling Information
10.3 NIOSH Analytical Methods 4,4'-METHYLENEDIANILINE 5029 from NIOSH Manual of Analytical Methods
11 Safety and Hazards 11.1 Hazards Identification 11.1.1 GHS Classification
Signal: Danger GHS Hazard Statements Aggregated GHS information provided by 539 companies from 14 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies. H317 (100%): May cause an allergic skin reaction [Warning Sensitization, Skin] H341 (100%): Suspected of causing genetic defects [Warning Germ cell mutagenicity] H350 (100%): May cause cancer [Danger Carcinogenicity] H370 (100%): Causes damage to organs [Danger Specific target organ toxicity, single exposure] H373 (99.81%): Causes damage to organs through prolonged or repeated exposure [Warning Specific target organ toxicity, repeated exposure] H411 (98.14%): Toxic to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard] Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. Precautionary Statement Codes P201, P202, P260, P261, P264, P270, P272, P273, P280, P281, P302+P352, P307+P311, P308+P313, P314, P321, P333+P313, P363, P391, P405, and P501 (The corresponding statement to each P-code can be found here.) from European Chemicals Agency - ECHA View all (4) GHS Classification entries
11.1.2 Health Hazard Excerpt from ERG Guide 153 [Substances - Toxic and/or Corrosive (Combustible)]: TOXIC; inhalation, ingestion or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. (ERG, 2016) from CAMEO Chemicals Carcinogen from NJDOH RTK Hazardous Substance List
11.1.3 Fire Hazard Excerpt from ERG Guide 153 [Substances - Toxic and/or Corrosive (Combustible)]: Combustible material: may burn but does not ignite readily. When heated, vapors may form explosive mixtures with air: indoors, outdoors and sewers explosion hazards. Those substances designated with a (P) may polymerize explosively when heated or involved in a fire. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. (ERG, 2016) from CAMEO Chemicals Combustible. from ILO-ICSC
11.1.4 Hazards Summary 4,4'-Methylenedianiline is an industrial chemical that is not known to occur naturally. It is also commonly known as diaminodiphenylmethane or MDA. It occurs as a colorless to pale yellow solid and has a faint odor. 4,4'-Methylenedianiline is used mainly for making polyurethane foams, which have a variety of uses, such as insulating materials in mailing containers. It is also used for
making coating materials, glues, Spandex® fiber, dyes, and rubber. from CDC-ATSDR Toxic Substances Portal 4,4'-Methylenedianiline (MDA) is primarily used to produce 4,4'-methylenedianline diisocyanate and other polymeric isocyanates. Acute (short-term) oral and dermal exposure to MDA causes liver damage in humans and animals. MDA can irritate the skin and eyes in humans. No information is available on the chronic (long-term), reproductive, developmental, or carcinogenic effects of MDA in humans. In rats and mice exposed to the dihydrochloride salt of MDA in their drinking water, statistically significant increases in the incidence of several types of tumors, including liver and thyroid tumors, were reported. EPA has not classified MDA for carcinogenicity. The International Agency for Research on Cancer (IARC) has classified MDA as a Group 2B, possible human carcinogen. from EPA Air Toxics
11.1.5 Fire Potential Combustable when exposed to hear or flame. Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2436
from HSDB
11.1.6 Skin, Eye, and Respiratory Irritations Eye irritant Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2436
from HSDB
11.2 Safety and Hazard Properties 11.2.1 Flammability Combustible Solid from The National Institute for Occupational Safety and Health - NIOSH
11.2.2 NFPA Hazard Classification Health: 3. 3= Materials that, on short exposure, could cause serious temporary or residual injury, including those requiring protection from all bodily contact. Fire fighters may enter the area only if they are protected from all contact with the material. Full protective clothing, including self-contained breathing apparatus, coat, pants, gloves, boots, and bands around legs, arms, and waist, should be provided. No skin surface should be exposed. Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997., p. 325-68
from HSDB Flammability: 1. 1= This degree includes materials that must be preheated before ignition will occur, such as Class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause frothing that will extinguish the fire. Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997., p. 325-68
from HSDB Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997., p. 325-68
from HSDB
11.2.3 NFPA Fire Rating 1 from CAMEO Chemicals
11.2.4 NFPA Health Rating 2 from CAMEO Chemicals
11.2.5 Chemical Dangers NIOSH considers 4,4'-methylenedianiline be a potential occupational carcinogen. NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases CD-ROM. Department of Health & Human Services, Centers for Disease Prevention & Control. National Institute for Occupational Safety & Health. DHHS (NIOSH) Publication No. 2005-151 (2005)
from HSDB The substance is a weak base. Reacts violently with strong oxidants. from ILO-ICSC
11.2.6 OSHA Standards Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 10 ppb; 15 min Short-Term Exposure Limit: 100 ppb 40 CFR 1910.1050 (USDOL); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of February 18, 2009: http://www.ecfr.gov
from HSDB
11.2.7 NIOSH Recommendations NIOSH considers 4,4'-methylenedianiline to be a potential occupational carcinogen. NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases CD-ROM. Department of Health & Human Services, Centers for Disease Prevention & Control. National Institute for Occupational Safety & Health. DHHS (NIOSH) Publication No. 2005-151 (2005)
from HSDB NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concn. NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases CD-ROM. Department of Health & Human Services, Centers for Disease Prevention & Control. National Institute for Occupational Safety & Health. DHHS (NIOSH) Publication No. 2005-151 (2005)
from HSDB
11.3 First Aid Measures 11.3.1 First Aid EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. IMMEDIATELY call a hospital or poison control center even if no symptoms (such as redness or irritation) develop. IMMEDIATELY transport the victim to a hospital for treatment after washing the affected areas. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. IMMEDIATELY call a physician and be prepared to transport the victim to a hospital even if no symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. OTHER: Since this chemical is a known or suspected carcinogen you should contact a physician for advice regarding the possible long term health effects and potential recommendation for medical monitoring. Recommendations from the physician will depend upon the specific compound, its chemical, physical and toxicity properties, the exposure level, length of exposure, and the route of exposure. (NTP, 1992) from CAMEO Chemicals (See procedures) Eye:Irrigate immediately Skin:Soap wash immediately
Breathing:Respiratory support Swallow:Medical attention immediately from The National Institute for Occupational Safety and Health - NIOSH
11.3.2 Exposure First Aid IN ALL CASES CONSULT A DOCTOR! from ILO-ICSC
11.3.3 Inhalation First Aid Fresh air, rest. Refer for medical attention. from ILO-ICSC
11.3.4 Skin First Aid Remove contaminated clothes. Rinse and then wash skin with water and soap. Refer for medical attention . from ILO-ICSC
11.3.5 Eye First Aid First rinse with plenty of water for several minutes (remove contact lenses if easily possible), then refer for medical attention. from ILO-ICSC
11.3.6 Ingestion First Aid Rinse mouth. Refer for medical attention . from ILO-ICSC
11.4 Fire Fighting Measures 11.4.1 Fire Fighting Excerpt from ERG Guide 153 [Substances - Toxic and/or Corrosive (Combustible)]: SMALL FIRE: Dry chemical, CO2 or water spray. LARGE FIRE: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire-control water for later disposal; do not scatter the material. FIRE INVOLVING TANKS OR CAR/TRAILER LOADS: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. (ERG, 2016) from CAMEO Chemicals Use water spray, powder, foam, carbon dioxide. from ILO-ICSC
11.5 Accidental Release Measures 11.5.1 Isolation and Evacuation Excerpt from ERG Guide 153 [Substances - Toxic and/or Corrosive (Combustible)]: As an immediate precautionary measure, isolate spill or leak area in all directions for at least 50 meters (150 feet) for liquids and at least 25 meters (75 feet) for solids. SPILL: Increase, in the downwind direction, as necessary, the isolation distance shown above. FIRE: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. (ERG, 2016) from CAMEO Chemicals
11.5.2 Spillage Disposal Personal protection: complete protective clothing including self-contained breathing apparatus. Do NOT let this chemical enter the environment. Sweep spilled substance into sealable containers. If appropriate, moisten first to prevent dusting. Carefully collect remainder. Then store and dispose of according to local regulations. from ILO-ICSC
11.5.3 Cleanup Methods FACILITY AND PROCESS ARE DISCUSSED FOR REMOVAL OF METHYLENEDIANILINE. YOUNG DA, PARKER BG; REMOVAL OF METHYLENEDIANILINE FROM CHEMICAL PLANT WASTEWATER; REPORT; ISS BDX-613-1981; CONF-780455-1, 1978, 29 PP
from HSDB PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured & the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed & labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer, 1979., p. 15
from HSDB
11.5.4 Disposal Methods SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations. from HSDB PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds & specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods & recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer, 1979., p. 14
from HSDB PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous & organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer, 1979., p. 15
from HSDB PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp & carcinogenic wastes generated by this treatment conducted to & burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter & misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer, 1979., p. 15
from HSDB PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer, 1979., p. 16
from HSDB
PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols & thiosulfate. The reactivity of various alkylating agents varies greatly ... & is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness & safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer, 1979., p. 17
from HSDB
11.5.5 Other Preventative Measures PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food & beverage containers or utensils, & the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, & rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer, 1979., p. 8
from HSDB PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes & wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer, 1979., p. 8
from HSDB PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth & purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care & vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... & when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer, 1979., p. 8
from HSDB PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, & contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) & label fixed to it, giving date of test & avg air-flow measured. This test should be repeated periodically & after any structural changes. /Chemical Carcinogens/ Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer, 1979., p. 9
from HSDB PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological & cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer & hood should be devised before expt begun. When mixing diets, special protective clothing &, possibly, respirators may be required. /Chemical Carcinogens/ Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer, 1979., p. 9
from HSDB PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms & sides & fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, & monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type & amt of carcinogen & efficiency with which it can be removed. /Chemical Carcinogens/ Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer, 1979., p. 10
from HSDB
PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors & benches, & ... interior of fume hoods & airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple & sensitive. /Chemical Carcinogens/ Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer, 1979., p. 10
from HSDB PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with highefficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing & use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer, 1979., p. 10
from HSDB PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency & who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer, 1979., p. 11
from HSDB The worker should immediately wash the skin when it becomes contaminated. NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases CD-ROM. Department of Health & Human Services, Centers for Disease Prevention & Control. National Institute for Occupational Safety & Health. DHHS (NIOSH) Publication No. 2005-151 (2005)
from HSDB The worker should wash daily at the end of each work shift, and prior to eating, drinking, smoking, etc. NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases CD-ROM. Department of Health & Human Services, Centers for Disease Prevention & Control. National Institute for Occupational Safety & Health. DHHS (NIOSH) Publication No. 2005-151 (2005)
from HSDB Work clothing that becomes wet or significantly contaminated should be removed or replaced. NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases CD-ROM. Department of Health & Human Services, Centers for Disease Prevention & Control. National Institute for Occupational Safety & Health. DHHS (NIOSH) Publication No. 2005-151 (2005)
from HSDB Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases CD-ROM. Department of Health & Human Services, Centers for Disease Prevention & Control. National Institute for Occupational Safety & Health. DHHS (NIOSH) Publication No. 2005-151 (2005)
from HSDB SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. from HSDB SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. from HSDB SRP: Wastewater from contaminant suppression, cleaning of protective clothing/equipment, or contaminated sites should be contained and evaluated for subject chemical or decomposition product concentrations. Concentrations shall be lower than applicable environmental discharge or disposal criteria. Alternatively, pretreatment and/or discharge to a POTW is acceptable only after review by the governing authority. Due consideration shall be given to remediation worker exposure (inhalation, dermal and ingestion) as well as fate during treatment, transfer and disposal. If it is not practicable to manage the chemical in this fashion, it must meet Hazardous Material Criteria for disposal. from HSDB
11.6 Handling and Storage 11.6.1 Nonfire Spill Response Excerpt from ERG Guide 153 [Substances - Toxic and/or Corrosive (Combustible)]: ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. (ERG, 2016) from CAMEO Chemicals
11.6.2 Safe Storage Separated from strong oxidants and food and feedstuffs. Well closed. Store in an area without drain or sewer access. Provision to contain effluent from fire extinguishing. from ILO-ICSC
11.6.3 Storage Conditions MATERIALS WHICH ARE TOXIC AS STORED OR WHICH CAN DECOMPOSE INTO TOXIC COMPONENTS...SHOULD BE STORED IN A COOL WELL VENTILATED PLACE, OUT OF THE DIRECT RAYS OF THE SUN, AWAY FROM AREAS OF HIGH FIRE HAZARD, & SHOULD BE PERIODICALLY INSPECTED. INCOMPATIBLE MATERIALS SHOULD BE ISOLATED... Sax, N.I. Dangerous Properties of Industrial Materials. 4th ed. New York: Van Nostrand Reinhold, 1975., p. 922
from HSDB PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen & date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer, 1979., p. 13
from HSDB
11.7 Exposure Control and Personal Protection 11.7.1 REL Ca See Appendix A from The National Institute for Occupational Safety and Health - NIOSH
11.7.2 PEL [1910.1050] TWA 0.010 ppm ST 0.100 ppm from The National Institute for Occupational Safety and Health - NIOSH
11.7.3 IDLH A potential occupational carcinogen. (NIOSH, 2016) from CAMEO Chemicals Ca [N.D.] See: IDLH INDEX from The National Institute for Occupational Safety and Health - NIOSH
11.7.4 Threshold Limit Values
8 hr Time Weighted Avg (TWA): 0.1 ppm, skin. /4,4-Methylene dianiline/ American Conference of Governmental Industrial Hygienists TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH, 2008, p. 40
from HSDB Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. /4,4-Methylene dianiline/ American Conference of Governmental Industrial Hygienists TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH, 2008, p. 5
from HSDB A3; Confirmed animal carcinogen with unknown relevance to humans. /4,4-Methylene dianiline/ American Conference of Governmental Industrial Hygienists TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH, 2008, p. 40
from HSDB
11.7.5 Sources and Potential Exposure Occupational exposure to MDA is possible through inhalation and dermal contact during its commercial manufacture and use as an intermediate. In the late 1960s, some people were accidentally exposed by eating MDA-contaminated bread. from EPA Air Toxics
11.7.6 Assessing Personal Exposure Samples of urine can be tested to determine if exposure to MDA has occurred. from EPA Air Toxics
11.7.7 Inhalation Risk A harmful concentration of airborne particles can be reached quickly when dispersed. from ILO-ICSC
11.7.8 Effects of Short Term Exposure The substance may cause effects on the liver. This may result in liver impairment. from ILO-ICSC
11.7.9 Effects of Long Term Exposure Repeated or prolonged contact may cause skin sensitization. The substance may have effects on the liver. This substance is possibly carcinogenic to humans. from ILO-ICSC
11.7.10 Personal Protection (See protection codes) Skin:Prevent skin contact Eyes:Prevent eye contact Wash skin:When contaminated/Daily Remove:When wet or contaminated Change:Daily Provide:Eyewash, Quick drench from The National Institute for Occupational Safety and Health - NIOSH
11.7.11 Respirator Recommendations (See Appendix E) NIOSH At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration: (APF = 10,000) Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode (APF = 10,000) Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained positivepressure breathing apparatus Escape: (APF = 50) Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister having an N100, R100, or P100 filter. Click here for information on selection of N, R, or P filters. Any appropriate escape-type, self-contained breathing apparatus Important additional information about respirator selection from The National Institute for Occupational Safety and Health - NIOSH
11.7.12 Fire Prevention NO open flames. from ILO-ICSC
11.7.13 Exposure Prevention PREVENT DISPERSION OF DUST! AVOID ALL CONTACT! from ILO-ICSC
11.7.14 Inhalation Prevention Use ventilation (not if powder), local exhaust or breathing protection. from ILO-ICSC
11.7.15 Skin Prevention Protective gloves. Protective clothing. from ILO-ICSC
11.7.16 Eye Prevention Wear safety spectacles or face shield. from ILO-ICSC
11.7.17 Ingestion Prevention Do not eat, drink, or smoke during work. Wash hands before eating. from ILO-ICSC
11.7.18 Protective Equipment and Clothing Skin: Wear appropriate personal protective clothing to prevent skin contact. Eyes: Wear appropriate eye protection to prevent eye contact. Wash skin: The worker should immediately wash the
skin when it becomes contaminated. The worker should wash daily at the end of each work shift. Remove: Work clothing that becomes wet or significantly contaminated should be removed and replaced. Change: Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premise. Provide: Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] (NIOSH, 2016) from CAMEO Chemicals PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. ... gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer, 1979., p. 8
from HSDB Wear appropriate personal protective clothing to prevent skin contact. NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases CD-ROM. Department of Health & Human Services, Centers for Disease Prevention & Control. National Institute for Occupational Safety & Health. DHHS (NIOSH) Publication No. 2005-151 (2005)
from HSDB Wear appropriate eye protection to prevent eye contact. NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases CD-ROM. Department of Health & Human Services, Centers for Disease Prevention & Control. National Institute for Occupational Safety & Health. DHHS (NIOSH) Publication No. 2005-151 (2005)
from HSDB Eyewash fountains should be provided in areas where there is any possbility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases CD-ROM. Department of Health & Human Services, Centers for Disease Prevention & Control. National Institute for Occupational Safety & Health. DHHS (NIOSH) Publication No. 2005-151 (2005)
from HSDB Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases CD-ROM. Department of Health & Human Services, Centers for Disease Prevention & Control. National Institute for Occupational Safety & Health. DHHS (NIOSH) Publication No. 2005-151 (2005)
from HSDB Respirator Recommendations: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration: Assigned Protection Factor (APF)
Respirator Recommendation
APF = 10,000
Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode.
APF = 10,000
Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxillary selfcontained positive-pressure breathing apparatus.
NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases CD-ROM. Department of Health & Human Services, Centers for Disease Prevention & Control. National Institute for Occupational Safety & Health. DHHS (NIOSH) Publication No. 2005-151 (2005)
from HSDB Respirator Recommendations: Escape conditions: Assigned Protection Factor (APF)
Respirator Recommendation
APF = 50
Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister having an N100, R100, or P100 filter./Any appropriate escape-type, self-contained breathing apparatus
NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases CD-ROM. Department of Health & Human Services, Centers for Disease Prevention & Control. National Institute for Occupational Safety & Health. DHHS (NIOSH) Publication No. 2005-151 (2005)
from HSDB
11.8 Stability and Reactivity 11.8.1 Air and Water Reactions Oxidizes slowly in air in a reaction catalyzed by light. Somewhat hygroscopic. Insoluble in water. from CAMEO Chemicals
11.8.2 Reactive Group Amines, Aromatic from CAMEO Chemicals
11.8.3 Reactivity Profile 4,4'-DIAMINODIPHENYLMETHANE polymerizes if heated above 257° F. Incompatible with strong oxidizing agents. It is also incompatible with acids. Catalyzes isocyanate-alcohol and epoxide reactions. Flammable gaseous hydrogen may be generated in combination with strong reducing agents, such as hydrides. from CAMEO Chemicals
11.8.4 Reactivities and Incompatibilities Strong oxidizers. NIOSH. NIOSH Pocket Guide to Chemical Hazards & Other Databases CD-ROM. Department of Health & Human Services, Centers for Disease Prevention & Control. National Institute for Occupational Safety & Health. DHHS (NIOSH) Publication No. 2005-151 (2005)
from HSDB Strong oxidizers from The National Institute for Occupational Safety and Health - NIOSH
11.9 Transport Information 11.9.1 DOT Emergency Guidelines /GUIDE 153: SUBSTANCES - TOXIC and/or CORROSIVE (Combustible)/ Fire or Explosion: Combustible material: may burn but does not ignite readily. When heated, vapors may form explosive mixtures with air: indoors, outdoors and sewers explosion hazards. Those substances designated with a (P) may polymerize explosively when heated or involved in a fire. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. U.S. Department of Transportation. 2012 Emergency Response Guidebook. Washington, D.C. 2012
from HSDB /GUIDE 153: SUBSTANCES - TOXIC and/or CORROSIVE (Combustible)/ Health: TOXIC; inhalation, ingestion or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. U.S. Department of Transportation. 2012 Emergency Response Guidebook. Washington, D.C. 2012
from HSDB /GUIDE 153: SUBSTANCES - TOXIC and/or CORROSIVE (Combustible)/ Public Safety: CALL Emergency Response Telephone Number on Shipping Paper first. If Shipping Paper not available or no answer, refer to appropriate telephone number listed on the inside back cover. As an immediate precautionary measure, isolate spill or leak area in all directions for at least 50 meters (150 feet) for liquids and at least 25 meters (75 feet) for solids. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas. U.S. Department of Transportation. 2012 Emergency Response Guidebook. Washington, D.C. 2012
from HSDB /GUIDE 153: SUBSTANCES - TOXIC and/or CORROSIVE (Combustible)/ Protective Clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing that is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations
ONLY; it is not effective in spill situations where direct contact with the substance is possible. U.S. Department of Transportation. 2012 Emergency Response Guidebook. Washington, D.C. 2012
from HSDB /GUIDE 153: SUBSTANCES - TOXIC and/or CORROSIVE (Combustible)/ Evacuation: Spill: See Table 1 - Initial Isolation and Protective Action Distances for highlighted materials. For nonhighlighted materials, increase, in the downwind direction, as necessary, the isolation distance shown under "PUBLIC SAFETY". Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. U.S. Department of Transportation. 2012 Emergency Response Guidebook. Washington, D.C. 2012
from HSDB /GUIDE 153: SUBSTANCES - TOXIC and/or CORROSIVE (Combustible)/ Fire: Small Fire: Dry chemical, CO2 or water spray. Large Fire: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire-control water for later disposal; do not scatter the material. Fire involving Tanks or Car/Trailer Loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. U.S. Department of Transportation. 2012 Emergency Response Guidebook. Washington, D.C. 2012
from HSDB /GUIDE 153: SUBSTANCES - TOXIC and/or CORROSIVE (Combustible)/ Spill or Leak: ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. U.S. Department of Transportation. 2012 Emergency Response Guidebook. Washington, D.C. 2012
from HSDB /GUIDE 153: SUBSTANCES - TOXIC and/or CORROSIVE (Combustible)/ First Aid: Move victim to fresh air. Call 911 or emergency medical service. Give artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; give artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved and take precautions to protect themselves. U.S. Department of Transportation. 2012 Emergency Response Guidebook. Washington, D.C. 2012
from HSDB
11.9.2 Shipment Methods and Regulations No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ 49 CFR 171.2 (7/1/96)
from HSDB The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.6112 (1988)
from HSDB PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped & will resist attack from the carcinogen. Both bottle & the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies & airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer, 1979., p. 13
from HSDB PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary & secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen & is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container & the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest & most secure form of transport & notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC
Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer, 1979., p. 13
from HSDB
11.9.3 DOT ID and Guide 2651 153 from DOT Emergency Response Guidebook
11.9.4 DOT Label Poison from CAMEO Chemicals
11.9.5 Packaging and Labelling Do not transport with food and feedstuffs. Marine pollutant. from ILO-ICSC
11.9.6 EC Classification Symbol: T, N; R: 45-39/23/24/25-43-48/20/21/22-68-51/53; S: 53-45-61; Note: E from ILO-ICSC
11.9.7 UN Classification UN Hazard Class: 6.1; UN Pack Group: III from ILO-ICSC
11.9.8 Emergency Response NFPA Code: H2; F1; R0. from ILO-ICSC
11.10 Regulatory Information 11.10.1 CERCLA Reportable Quantities Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 10 lb or 4.54 kg. The toll free number of the NRC is (800) 424-8802. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). 40 CFR 302.4 (USEPA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of February 18, 2009: http://www.ecfr.gov
from HSDB
11.10.2 TSCA Requirements Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Benzenamine, 4,4'-methylenebis is included on this list. 40 CFR 716.120 (USEPA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of February 18, 2009: http://www.ecfr.gov
from HSDB
12 Toxicity 12.1 Toxicological Information 12.1.1 NIOSH Toxicity Data Download 1 to 5 of 49
View More
Measurement
Route/Organism
Dose
Effect
Date
Skin and Eye Irritation
eye /rabbit
100 mg/24H
moderate
October 2015
Skin and Eye Irritation
skin /child
0.5%/2D
October 2015
Skin and Eye Irritation
skin /man
0.5%/2D
October 2015
Skin and Eye Irritation
skin /woman
0.5%/2D
October 2015
fibroblast/hamster
125 mg/L/3H
October 2015
Mutation Data
System
Cytogenetic Analysis
from The National Institute for Occupational Safety and Health - NIOSH
12.1.2 Carcinogen No data are available in humans. Sufficient evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 2B: The agent is possibly carcinogenic to humans. IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php , p. S7 66 (1987)
from HSDB A3; Confirmed animal carcinogen with unknown relevance to humans. /4,4-Methylene dianiline/ American Conference of Governmental Industrial Hygienists TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH, 2008, p. 40
from HSDB 4,4'-Methylenedianiline: reasonably anticipated to be a human carcinogen. DHHS/National Toxicology Program; Eleventh Report on Carcinogens: 4,4'-Methylenedianiline (101-77-9) (January 2005). Available from, as of July 31, 2009: http://ntp.niehs.nih.gov/ntp/roc/eleventh/profiles/s108meth.pdf
from HSDB
12.1.3 Exposure Routes The substance can be absorbed into the body by inhalation of its aerosol, through the skin and by ingestion. from ILO-ICSC inhalation, skin absorption, ingestion, skin and/or eye contact from The National Institute for Occupational Safety and Health - NIOSH
12.1.4 Symptoms irritation eyes; jaundice, hepatitis; myocardial damage; In Animals: heart, liver, spleen damage; [potential occupational carcinogen] from The National Institute for Occupational Safety and Health - NIOSH
12.1.5 Inhalation Symptoms Nausea. Vomiting. Abdominal pain. Fever.
from ILO-ICSC
12.1.6 Skin Symptoms MAY BE ABSORBED! Further see Inhalation. from ILO-ICSC
12.1.7 Ingestion Symptoms Jaundice. Further see Inhalation. from ILO-ICSC
12.1.8 Target Organs Hepatic (Liver) from CDC-ATSDR Toxic Substances Portal Eyes, liver, cardiovascular system, spleen from The National Institute for Occupational Safety and Health - NIOSH
12.1.9 Cancer Sites [in animals: bladder cancer] from The National Institute for Occupational Safety and Health - NIOSH
12.1.10 Acute Effects Acute oral and dermal exposure to MDA causes liver damage in humans and animals. MDA is a causative agent in "Epping Jaundice," which has symptoms including jaundice, tender liver, weakness, abdominal pain, nausea, vomiting, headache, fever, chills, and muscle pain in humans. MDA can irritate the skin and eyes in humans. A single oral exposure to MDA caused liver damage in rats. Tests involving acute exposure of rats, mice, and rabbits have demonstrated MDA to have moderate acute toxicity from oral exposure. from EPA Air Toxics
12.1.11 Chronic Effects No information is available on the chronic effects of MDA in humans. Damage to the liver and thyroid, mineralization in the kidneys, and reduced body weight gain have been observed in rats and mice chronically exposed to MDA in their diet. EPA has not established a Reference Concentration (RfC) or a Reference Dose (RfD) for MDA. The California Environmental Protection Agency (CalEPA) has calculated a chronic inhalation reference exposure level of 0.02 milligrams per cubic meter (mg/m3 ) based on ocular effects in guinea pigs. The CalEPA reference exposure level is a concentration at or below which adverse health effects are not likely to occur. It is not a direct estimator of risk but rather a reference point to gauge the potential effects. At lifetime exposures increasingly greater than the reference exposure level, the potential for adverse health effects increases. ATSDR has calculated an intermediate oral minimal risk level (MRL) of 0.08 milligrams per kilogram body weight per day (mg/kg/d) based on liver effects in rats. The MRL is an estimate of the daily human exposure to a hazardous substance that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration of exposure. from EPA Air Toxics
12.1.12 Cancer Risk No information is available on the carcinogenic effects of MDA in humans. In rats and mice exposed to MDA (as a dihydrochloride salt) in their drinking water, statistically significant increases in the incidence of several types of tumors, including liver and thyroid
tumors, were reported. EPA has not classified MDA for carcinogenicity. IARC has classified MDA as a Group 2B, possible human carcinogen. CalEPA has calculated an oral cancer slope factor of 1.6 (mg/kg/d)-1 . from EPA Air Toxics
12.1.13 Reproductive and Developmental Effects No adequate information is available on the reproductive or developmental effects of MDA in humans or animals. from EPA Air Toxics
12.1.14 Interactions Four antioxidant species, butylated hydroxyanisole, butylated hydroxytoluene, ethoxyquin and alpha-tocopherol, and three other compounds, 4,4'-diaminodiphenylmethane, acetaminophen and glutathione, were tested for inhibitory effects on hepatocarcinogenesis in male F344 rats. Rats were initially given a single ip injection of diethylnitrosamine (200 mg/kg body weight) and fed a basal diet containing 0.02% 2-acetylaminofluorene from week 2 to week 8. Animals were subjected to partial hepatectomy at the end of week 3. From week 12 to week 36, they were given a basal diet containing 2% butylated hydroxyanisole, 1% butylated hydroxytoluene, 0.8% ethoxyquin, 1% alpha-tocopherol, 0.1% 4,4'-diaminodiphenylmethane, 1% acetaminophen, or 1% glutathione, then killed at week 40, 4 weeks after cessation of treatment with the test chemicals. The incidence of hepatocellular carcinoma was significantly decreased in the groups given ethoxyquin or 4,4'-diaminodiphenylmethane. Quantitative analysis of the number and area of hepatocellular carcinoma per unit liver area revealed a significant decrease in the area of hepatocellular carcinoma in the groups given ethoxyquin, 4,4'-diaminodiphenylmethane or acetaminophen. The results suggest that ethoxyquin, 4,4'-diaminodiphenylmethane and acetaminophen exerted an inhibitory effect on the development of hepatocellular carcinoma, while butylated hydroxyanisole, butylated hydroxytoluene, alpha-tocopherol and glutathione had no significant effect. Abstract: PubMed Masui T et al; Jpn J Cancer Res 77(3): 231-7 (1986)
from HSDB The modifying effects of 4,4'-diaminodiphenylmethane (0.1% in diet) administration on liver carcinogenesis induced by 2-acetylaminofluorene (0.02% in diet), 3'-methyl- 4dimethylaminoazobenzene (0.06% in diet), diethylnitrosamine (0.001% in drinking water) and N-ethyl-N-hydroxyethylnitrosamine (0.1% in drinking water), N-ethyl-N-hydroxyethylnitrosamine induced esophagus and kidney carcinogenesis, and forestomach carcinogenesis induced by butylated hydroxyanisole (1.0% in diet) were examined in F344 male rats. Mean survival time tended to be longer in 4,4'-diaminodiphenylmethane supplemented groups, the difference being significant in diethylnitrosamine + 4,4'-diaminodiphenylmethane and N-ethyl-N-hydroxyethylnitrosamine + 4,4'-diaminodiphenylmethane groups. Intake of carcinogens was slightly but not significantly reduced by 4,4'-diaminodiphenylmethane. The incidences of hyperplastic nodules and hepatocellular carcinomas were significantly decreased in 2-acetylaminofluorene or 3'-methyl-4-dimethylaminoazobenzene + 4,4'-diaminodiphenylmethane groups. Pulmonary metastases were also less common in 3'-methyl-4-dimethylaminoazo benzene or N-ethyl-N-hydroxyethylnitrosamine + 4,4'-diaminodiphenylmethane groups. Development of papillomas in the esophagus but not in tumors in the forestomach was also inhibited by 4,4'-diaminodiphenylmethane. Inhibition in the different organs was not significantly related to decrease in body weight or carcinogen intake, indicating a mechanism independent of non-specific toxic effects or reduction in food consumption. Some other factors possibly related to its ability to cause bile duct proliferation and/or altered activity of enzymes relevant to drug metabolism may be involved. Abstract: PubMed Tsuda H et al; Carcinogenesis 8(5): 719-22 (1987)
from HSDB Limited data in animals showed that pretreatment of rats with the monooxygenase function inhibitor aminobenzotriazol, ameliorated the hepatic effects of 4,4'- methylenedianiline. However, pretreatment with the inhibitor SKF-525A had no effect. Based on these results, the investigators proposed that 4,4'-methylenedianiline requires metabolic activation for its toxicity and that activation is carried out by an isozyme of cytochrome P-450 that is inhibited by aminobenzotriazol, but not SKF-525A. DHHS/ATSDR; Toxicological Profile for Methylenedianiline (PB/99/102568/AS) (August 1998). Available from, as of February 23, 2009: http://www.atsdr.cdc.gov/toxpro2.html#bookmark05
from HSDB
12.1.15 Antidote and Emergency Treatment Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand-valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR as necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Nitrates, nitrites, and related compounds/ Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 286
from HSDB Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for shock and treat if necessary ... . Anticipate seizures and treat as necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of
water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Nitrates, nitrites, and related compounds/ Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 286-7
from HSDB Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or is in severe respiratory distress. Monitor cardiac rhythm and treat arrhythmias if necessary. Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. If unresponsive to these measures, vasopressors may be helpful. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Administer 1% solution methylene blue if patient is symptomatic with severe hypoxia, cyanosis, and cardiac compromise not responding to oxygen. DIRECT PHYSICIAN ORDER ONLY ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Nitrates, nitrites, and related compounds/ Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 287
from HSDB
12.1.16 Medical Surveillance IT IS RECOMMENDED THAT REGULAR LIVER /FUNCTION/ TESTS BE PERFORMED ON WORKERS COMING IN CONTACT WITH /DIAMINODIPHENYLMETHANE/. GOHLKE R; Z GESAMTE HYG IHRE GRENZGEB 24 (3): 159 (1978)
from HSDB PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer, 1979., p. 23
from HSDB
12.1.17 Human Toxicity Excerpts /HUMAN EXPOSURE STUDIES/ Five healthy volunteers /were exposed/ dermally for 1 hr to 0.75-2.25 umol MDA dissolved in isopropanol, by use of a patch-test technique. Determination of MDA remaining in the patch units after exposure showed that a median of 28% (range 25-29%) was absorbed. After hydrolyzing MDA has been determined in plasma with an initial peak and a decline after removing the patch. MDA was also detected in hydrolyzed urine. The maximum rate of MDA excretion in urine was found 6-11 hours after the onset of exposure. Within two subjects studied at three doses, the urinary excretion was proportional to the exposure. The elimination half-lives in plasma and urine had medians at 13 and 7 hours, respectively. In eight out of nine exposures, the elimination half-life was longer in plasma than in urine. Slow acetylation seemed to be associated with short elimination half-life in urine. The median of total MDA amount excreted in urine during 48 hours, was 33 nmol for the five subjects exposed to 0.75 umol, which corresponds to roughly 16% (range 2%-26%) of the absorbed dose. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /HUMAN EXPOSURE STUDIES/ A study examined the significance of positive patch test reactions to 0.5% MDA. Data of 202 MDA-positive patients concerning age, sex and profession, type, localization and duration of eczema and combined allergens were evaluated. The results were compared with those of 3397 consecutive, unselected, contact dermatitis patients with negative reactions to MDA. /It was/ reported /that/ a case of skin reaction induced by MDA in a man who cleaned a gutter in a chemical plant which contained MDA. He developed an extensive red, itchy, papular, and vesicular eruption, with a toxic/allergic appearance involving the face, neck and wrists. A broad spectrum of reactions was obtained, apparently based on cross-sensitizing groups (para-group sensitivity). All test concentrations of MDA revealed a positive reaction. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /HUMAN EXPOSURE STUDIES/ Patch testing indicated that a large number of patients with contact dermatitis were sensitized to MDA. Primary contact dermatitis due to hair cosmetics was diagnosed in 52 from a total of 8230 patients with eczematous dermatitis. Positive patch tests were obtained in 34 cases, of which 15 were positive patch-tested with MDA. The remaining 18 cases were considered as likely instances of contact irritation. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /HUMAN EXPOSURE STUDIES/ In 1988, 576 consecutive patients of the Allergology Center in Italy were tested with the standard series: 22 (38%) positive patch-test results to MDA were noted. MDA was the fourth most common allergen after nickel, cobalt and potassium dichromate. 4140 patients from eight skin hospitals were patch tested. A sensitization was found in 47% of the people tested. 3.3% of 4140 patients with contact dermatitis gave positive patch tests with MDA. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /SIGNS AND SYMPTOMS/ Human exposure to MDA, via dermal, inhalation, or oral routes, may result in a variety of toxic effects that include fever, hyperthermia, discolored urine, skin rash, allergic dermatitis, and bile duct epithelial damage resulting in jaundice, hepatitis, cholestasis, cholangitis, bile duct proliferation, myocardiopathy, and impaired visual acuity... /4,4'Methylenedianiline/
Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V4:1073
from HSDB /CASE REPORTS/ A case of toxic allergic skin reaction, secondary to accidental contact with methylenedianiline in a cleaner at a chemical factory was reported. An extensive red, itchy, papular and vesicular rash developed on the face, neck, and wrists of a 32 year old cleaner several hours after cleaning a shallow gutter in a chemical facility with a high pressure water hose. The cleaner was wearing protective clothing including gloves, apron, safety goggles and a cap during the cleaning operation. Among the chemicals present in the gutter, two were suspected as the causative agent, epichlorohydrin and methylenedianiline. Patch testing revealed a strong positive reaction to methylenedianiline and epoxy resin, and a broad spectrum of reactions apparently due to cross sensitization to para groups. The patch test with epichlorohydrin was negative. It was concluded that occupational exposure to methylenediamine, used as a catalyst in the production of polyurethanes, as a hardener or curing agent for epoxy resins, and as an antioxidant in the manufacture of synthetic fibers, should be avoided because of its sensitization capability and possible cross sensitization with azo dyes. Abstract: PubMed Van Joost T et al; Contact Dermatitis 16(5): 246-8 (1987)
from HSDB /CASE REPORTS/ The most notable instance of MDA poisoning was the so called "Epping Jaundice," in which 84 people living in the Epping area, England, in 1965 suffered ill effects caused by eating bread baked with a flour contaminated by MDA. From analysis of the MDA content of bread samples it has been estimated that the dose of MDA received by these individuals was about 3 mg/kg. Symptoms appeared within hours to a few days of eating the bread; they were somewhat variable, but in most cases comprised upper abdominal pain, followed by aches and jaundice. Serum clinical chemistry measurements indicated elevated levels of bilirubin, alkaline phosphatase and aspartate aminotransferase. Liver biopsy revealed damage to the parenchyma and the biliary tree. In the early stages the characteristic lesion was inflammation, which progressed later to centrilobular cholestasis and hepatocellular necrosis and degeneration. There were no fatalities, all patients recovering within a period of several weeks. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /CASE REPORTS/ Between 1966 and 1972 acute febrile illness associated with jaundice and rash developed in 12 young male workers who added powdered MBA to an epoxy resin formulation in a hot roller mill. Experience before and after the provision of respiratory protection equipment suggested that percutaneous absorption was the primary route of exposure in these cases. A further case was also reported: an employee of another company contracted to pulverize the flake form of MDA. Hepatitis developed within 3 days of commencing this type of work. In all these cases the subjects appeared to make a complete recovery and returned to work within 10 weeks of the onset of symptoms. When re-examined 9 months to 5.5 years later, all were apparently in good health. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /CASE REPORTS/ In another case report of accidental drinking of an unknown quantity of a solution of MDA in potassium carbonate and butyrolactone, myocardial effects (ECG chances, bradycardia, hypotension) were indicated. Furthermore, jaundice with elevated serum aminotransferase and bilirubin levels, hematuria and glycosuria were reported. The particular, persistent retinal damage in the eyes were also noted. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /CASE REPORTS/ ... /Investigators/ report six participants of a technoparty (1 female, 5 males, ages 17-25) who were admitted to the hospital with severe colicky abdominal pain and subsequently developed symptoms of hepatotoxicity. They had ingested an alcoholic beverage that had been spiked with a powdery substance they dubbed MDA. All patients showed similar clinical symptoms, with an identical time course. Acute jaundice developed within 2 days after ingestion. Enzymes indicating cholestasis increased steadily over 7 days and reached peak values of 800 U/L (AP) and 380 U/L (GGT), whereas transaminases remained moderately elevated. Between days 5 and 7, all patients became febrile for one day, their body temperatures rising up to 40 degrees C. There was no evidence for hemolysis or an infectious hepatitis. Toxicological analysis revealed the presence of p,p'-diaminodiphenylmethane (4,4'-methylenedianiline) at a concentration of 130 mg/L in one of two urine extracts examined. ... Abstract: PubMed Tillmann, HL et al; Journal of Toxicology 35 (1): 35-40 (1997)
from HSDB /CASE REPORTS/ The case of 6 workmen engaged in laying an epoxy resin based floor /was reported/: Four of these men developed an acute hepatic illness after a single exposure, in two of them recurring on re-exposure to MDA a few months later. Again they were most severely affected with nausea, myalgia, pain in the chest and abdomen, and showed dark urine. Liver function tests gave grossly abnormal results. One of these men, when examined after 14 months, and after a further 4 months, still complained of a variety of symptoms, and his liver was palpable. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /CASE REPORTS/ A young man suffered an acute exposure to MDA dust with oral, dermal, and /respiratory/ absorption of the substance due to an air filter malfunction: The next morning he had severe supraumbilical pain, and proritic macular rash encircling both forearms up to sleeve level. He exhibited jaundice and electrocardiogram abnormalities suggesting myocardial injury, both effects resulting from the MDA exposure. After 3 months the clinical asymptomatic patient still gave ECG evidence of myocardial residua, and after 1 year the ECG was normal. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /CASE REPORTS/ A case of two women employed in a small polyurethane molding plant /was reported when they/ developed extensive pruritic, papular, and/or vesicular eruption on face and neck, when molding polyurethan plastic. Patch tests gave positive reactions to prepolymers based on methylene bis (4-cyclohexylisocyanate), and also to MDA which was used as a catalyst.
European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /CASE REPORTS/ There is a single case report of a worker handling an MDA-containing insulating material who developed an apparent skin photosensitivity to MDA, observed during diagnostic photopatchtesting. A 39-year-old telephone service installer, skin type IV, who works outdoors climbing telephone poles, developed an erythematous, pruritic dermatitis. This occurred on his uncovered arms and forearms, but not on his hands which were covered by gloves, in the summer months, and cleared when he was not working. Phototesting revealed a decreased minimal erythema dose, and no abnormal reaction or erythema to UVA. Photopatch tests were positive for MDA. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /CASE REPORTS/ Four cases of acute intoxications /were reported/ with MDA in workers resulting in an acute hepatic illness. In two of these men the illness recurred on re-exposure a few months later and their reconvalescence period was prolonged. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /CASE REPORTS/ Clinical hepatitis related to MDA exposure was reported. Six cases out of 300 men who applied epoxy resins as a surface coat at a plant construction site showed elevated serum transaminases and bilirubin. The liquid epoxide was mixed with a dry powder containing methylenedianiline. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /CASE REPORTS/ A male subject developed eosinophilia with left shift in neutrophils 7-35 days after accidentally ingesting a solution containing 4,4'- methylenedianiline, potassium carbonate, and gamma-butyrolactone. This is consistent with the appearance of erythema multiform which is characterized by eosinophilia. DHHS/ATSDR; Toxicological Profile for Methylenedianiline (PB/99/102568/AS) (August 1998). Available from, as of February 23, 2009: http://www.atsdr.cdc.gov/toxpro2.html#bookmark05
from HSDB /CASE REPORTS/ A recent study reports that an 18-year-old male had mild leucocyte elevation 1 day after drinking an alcoholic beverage spiked with 4,4'-methylenedianiline; his blood cell count and thrombocyte rate were normal. The amount of 4,4'-methylenedianiline ingested was not known. DHHS/ATSDR; Toxicological Profile for Methylenedianiline (PB/99/102568/AS) (August 1998). Available from, as of February 23, 2009: http://www.atsdr.cdc.gov/toxpro2.html#bookmark05
from HSDB /CASE REPORTS/ Thirteen cases of toxic hepatitis were reported in a factory that manufactured hard plastic. 4,4'-Methylenedianiline was used as a curing agent in the process. The illness began between one and three weeks after employment started and all the reported signs and symptoms were consistent with liver disease (right upper quadrant pain and fever, jaundice, elevated transaminases, hyperbilirubinemia). Similar findings have also been described by others. All these cases shared common signs and symptoms that included pain, elevated serum transaminases, jaundice, and hyperbilirubinemia. DHHS/ATSDR; Toxicological Profile for Methylenedianiline (PB/99/102568/AS) (August 1998). Available from, as of February 23, 2009: http://www.atsdr.cdc.gov/toxpro2.html#bookmark05
from HSDB /CASE REPORTS/ A young man drank what was said to be a solution of MDA in potassium carbonate and gamma-butyrolactone. After 4 days the patient's vision became blurred, and it continued to worsen although the fundi were normal. A presumptive diagnosis of toxic optic neuropathy was followed by the ineffective treatment with prednisolone. After 3 weeks he had only a perception of light. Shortly afterwards improvement began, and he could see reasonably well at about 3 months after the accident. At that time there was gross malfunction of the retinal epithelium with impaired acuity, and severe loss of the central visual field, color discrimination, and dark adaptation. There was little improvement 18 months later. A mild sensory peripheral neuropathy was demonstrated in day 13, and it resolved over several weeks. On day 2 the man developed a mild fever, and transaminases and bilirubin were elevated. The hyperbilirubinaemia was predominantly conjugated. On day 3 he developed jaundice, and by day 10 he needed a diabetic diet to control his blood sugar. His urine contained cystathionine, which may be found secondary to hepatocellular dysfunction. Target cells were seen in his peripheral blood, with eosinophilia, and a left shift in his neutrophils. His systemic symptoms slowly resolved. He developed pruritis and slight hepatomegaly after 6 weeks, but this quickly resolved, with the disappearance of jaundice 2-3 weeks later. After about 3 months he was asymptomatic, except for his visual problems, but transaminases remained elevated after 1 yr. European Commission, ESIS; IUCLID Dataset, 4,4-Diaminodiphenylmethane (101-77-9) p 147 (2000 CD-ROM edition). Available from, as of March, 5 2009: http://esis.jrc.ec.europa.eu/
from HSDB /CASE REPORTS/ ... Five workers in an industrial waste plant developed acute toxic hepatitis, one of whom died after 3 months due to fulminant hepatitis. In the plant, /investigators/ detected several chemicals with hepatotoxic potential, including pyridine, dimethylformamide, dimethylacetamide, and methylenedianiline. The workers had been working in the high-vapor-generating area of the plant, and the findings of pathologic examination showed typical features of acute toxic hepatitis. Infectious hepatitis and drug-induced hepatitis were excluded by laboratory findings, as well as the clinical course of hepatitis. All cases of toxic hepatitis in this plant developed after the change of the disposal process to thermochemical reaction-type treatment using unslaked lime reacted with industrial wastes. During this chemical reaction, vapor containing several toxic materials was generated. Although /investigators/ could not confirm the definitive causative chemical, we suspect that these cases of hepatitis were caused by one of the hepatotoxic agents or by a synergistic interaction among several of them. ...[Cheong, Het al; Environmental Health Perspectives 115 (1): 107-112 (2007)] Full text: PMC1797842 Abstract: PubMed from HSDB /SURVEILLANCE/ ... Between 1967 and 1976, 10 workers at a plant in Ontario that used MDA as an epoxy hardener developed acute jaundice. /Investigators/ followed this group from the date of intoxication through to the end of 1991 for cancer incidence by matching with the Ontario Cancer Registry. To date, one cancer, a pathologically confirmed bladder cancer has developed
(expected number based on provincial incidence rates: 0.64 for all cancers, 0.05 for bladder cancer). This finding may be important because bladder cancer was a site of interest a priori; bladder cancers have been observed in two other occupationally exposed groups (significantly higher than expected in one of these)... Abstract: PubMed Liss, GM et al; American journal of industrial medicine 26 (1): 117-124 (1994)
from HSDB /SURVEILLANCE/ /Researchers/ performed a follow-up investigation of 179 white male deaths among employees with potential exposure to epoxy resins and amine hardeners who had ever worked for more than 1 month in areas with potential exposure to MDA. 46 persons of this group died with malign neoplasms. The proportional mortality rate amongst these persons revealed a statistically significant excess for cancer of large intestine, cancer of bladder, lymphosarcoma and reticulosarcoma compared to the whole population. In a proportional cancer mortality ratio analysis only the excess of bladder cancer remained significantly elevated. On the basis of these findings NIOSH suggests an association between bladder cancer and work in areas with past or present potential exposure to MDA. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /SURVEILLANCE/ A retrospective assessment of exposure and cancer morbidity was conducted in power generation workers exposed to an epoxy resin containing 35% 4,4'-methylenedianiline in Sweden. The cohort was composed of 550 males and 45 females. Based on company records, the individuals were subdivided into three categories: exposed, possibly exposed, and unexposed. Information on the cancer incidence of the cohort was obtained by computerized matching with the national cancer register for the period 1964-1985. Standardized incidence ratios (SIR) were obtained from the ratio of the observed to the expected number of cases. Exposure was considered to be primarily by the dermal route. In all three male groups, the observed number of cancers for all sites and for urinary bladder cancer was lower than the observed number. The overall SIR was 0.52 based on 5 observed cases. In the male exposed subgroup, no single cancer case appeared throughout the observation period; the expected number was 3. Among the female workers, 2 cancer cases were identified (none in the urinary bladder); 2.7 cancer cases (all cancers) had been expected from the national rates. The authors indicate that the results should be interpreted with caution since the cohort was small, the majority of the subjects were quite young and had not reached cancer-prone age, and the follow-up period was short and may have not covered the latency period for bladder cancer (20 years). DHHS/ATSDR; Toxicological Profile for Methylenedianiline (PB/99/102568/AS) (August 1998). Available from, as of February 23, 2009: http://www.atsdr.cdc.gov/toxpro2.html#bookmark05
from HSDB /BIOMONITORING/ The exposure to MDA was assessed in workers in 10 French firms by measuring urinary MDA excretion levels. Analysis of 368 post-shift urine samples collected from 133 workers reveals that urinary excretion of MDA is much higher in workers handling flaked MDA than in those handling MDA in solution (44% and 8% of values, respectively, in excess of 50 ug/L). The mean rates were 140 ug/L for the four factories using flaked MDA and 13 ug/L for the six factories using liquid formulations, with values ranging from 58 to 197 ug/L and from /less than/ 2 to 33 ug/L respectively. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /BIOMONITORING/ In addition to the analysis of urine samples for MDA and acetylated metabolites, the ability of MDA to bind to hemoglobin is used for biological monitoring ... After occupational contact with MDA concentrations below 100 ig MDA/cu m a dose-dependent increase of MDA in urine and the erythrocytic Hb adduct has been observed. The data shows a good correlation between the MDA excretion in urine and the Hb adducts in erythrocytes. However, there is no linear correlation between the air values and the biological values. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /BIOMONITORING/ ... /Investigators/ monitored biological samples from 45 4,4'-methylenediphenyl diisocyanate (MDI) exposed and 40 non-exposed construction site workers. 4,4'Methylenedianiline (MDA) and N-acetyl-4,4'-MDA (AcMDA) were determined from untreated urine (U-MDA, U-AcMDA) and MDA was analysed from acid-treated urine (U-MDA-tot). Hemoglobin (Hb) adducts of MDA (Hb-MDA) were determined in all workers. The levels of biomarkers decreased in the following order: U-MDA-tot>U-AcMDA>U-MDA>Hb-MDA. The same order was found for the percentage of samples, which were found positive in exposed workers: 100%, 91%, 91%, 27%. The urine levels U-MDA-tot correlate with U-MDA, U-AcMDA and Hb-MDA with r =0.79, 0.86 and 0.39, respectively (Spearman rank order, p<0.01). U-AcMDA correlates with U-MDA and Hb-MDA with r=0.77 and 0.47, respectively (p<0.01). U-MDA correlates with Hb-MDA (r=0.38, p<0.05). The levels in the controls were significantly lower than in the exposed workers for all compounds (Mann-Whitney test, p<0.01). ... Abstract: PubMed Sabbioni, G et al; Biomarkers 12 (5): 468-483 (2007)
from HSDB /BIOMONITORING/ ... Workers /were/ exposed to low levels of MDA. Adducts and metabolites were analyzed by gas chromatography-mass spectrometry after hydrolysis, extraction and derivatization. Hb adducts of MDA were detected in 31 out of the 33 MDA workers and both MDA and N-acetyl-MDA (AcMDA) were found in 20 of these individuals. In the urine of workers exposed to MDA both MDA and AcMDA were found in all samples, with the exception of five where only MDA was detected. Acid hydrolysis of the urine samples yielded an approximately 3-fold higher concentration of MDA than the sum of MDA and AcMDA found after base hydrolysis. MDA but not AcMDA found in urine and in Hb correlate well, except for three outliers. In one worker the Hb adduct level of MDA was very low compared to the urine levels. Two workers had very high levels of MDA as Hb adducts but very low levels as urine metabolites. The former case indicates that the workers were recently exposed to higher levels of MDA. The latter case suggests a relatively low recent exposure. The air levels of MDA, monitored using personal air monitors, were below the detection limit. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /BIOMONITORING/.../A/ biomonitoring study of /4,4'-Methylenediphenyl diisocyanate/ workers showed the presence of /4,4'-Methylenedianiline/ (MDA) and its N-acetyl metabolite as albumin adducts, hemoglobin adducts, and urinary metabolites. Animal study also showed DNA adducts with MDA in the olfactory epithelium of rats exposed to atmosphere containing MDI. /4,4'Methylenedianiline/
Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. V4:1073
from HSDB /GENOTOXICITY/ Four chemicals that are known to induce in rats thyroid follicular-cell adenomas and carcinomas were assayed for their ability to induce DNA damage and DNA repair synthesis in primary cultures of human thyroid cells. Significant dose-dependent increases in the frequency of DNA single-strand breaks and alkali-labile sites, as measures by the Comet assay, were obtained after a 20-h exposure to the following subtoxic concentrations of the four test compounds: 2,4-diaminoanisole (DAA) from 0.10 to 1.0 mM, 4,4'-methylene-bis(N,N-dimethyl)benzenamine (MDB) from 0.32 to 1.8 mM, propylthiouracil (PTU) from 1.8 to 5.6 mM, and 4,4'-thiodianiline (THA) from 0.032 to 0.18 mM. Under the same experimental conditions, DNA repair synthesis, as evaluated by quantitative autoradiography, was present in thyreocytes exposed to DAA but absent after treatment with MDB, PTU, and THA. Consistent with their thyroid-specific carcinogenic activity, all the four chemicals, administered p.o. in rats in a single dose corresponding to 1/2 LD50, induced a statistically significant degree of DNA fragmentation in the thyroid, whereas any substantial evidence of DNA lesions was absent in liver, kidney, and lung, which, with the exception of liver tumors caused by THA, are not targets of the carcinogenic activity of the four test compounds. ... Abstract: PubMed Mattioli, F et al; Toxicology and applied Pharmacology 203 (2): 99-105 (2005)
from HSDB /GENOTOXICITY/ 4,4'-Methylenedianiline (MDA), an aromatic amine used in various industrial processes and previously found to induce tumor development in liver and thyroid of mice and rats, was evaluated for its DNA-damaging activity in primary cultures of hepatocytes and thyreocytes from rat and human donors. After exposure for 4 and 20 hr to MDA concentrations ranging from 10 to 180 microM, a statistically significant increase in the frequency of DNA lesions was revealed by the Comet assay in primary hepatocytes and thyreocytes from donors of both species, the response being dose dependent up to 56-100 microM MDA. DNA fragmentation was more marked after 4 than after 20 hr exposure in all four cell types. DNA was damaged to a lesser extent in human hepatocytes and thyreocytes than in corresponding rat cells and in both species in hepatocytes than in thyreocytes. In both rat and human hepatocytes a 20-hr exposure to the same MDA concentrations elicited a modest amount of DNA repair synthesis, as evaluated by autoradiography. Evidence of a partial reduction of DNA damage, and therefore of only partial DNA repair, was observed in rat hepatocytes and in rat and human thyreocytes incubated for 16 hr in MDA-free medium after a 4-hr MDA treatment. A 4-hr exposure to 56, 100, and 180 microM MDA did not induce DNA lesions in primary cultures of cells from three rat organs, kidney, urinary bladder mucosa, and brain, which are resistant to MDA carcinogenic activity. Under the same experimental conditions any evidence of DNA damage was absent in primary kidney and urinary bladder cells from human donors. Abstract: PubMed Martelli, A et al; Toxicology and applied pharmacology 182 (3): 219-225 (2002)
from HSDB
12.1.18 Non-Human Toxicity Excerpts /LABORATORY ANIMALS: Acute Exposure/ 4,4'-DIAMINODIPHENYLMETHANE @ 0.083 G/KG ORALLY WAS INJURIOUS TO LIVER & SPLEEN OF RATS. Abstract: PubMed PLUDRO ET AL; ACTA POL PHARM 26 (4): 353 (1969)
from HSDB /LABORATORY ANIMALS: Acute Exposure/ Large interspecies differences with regard to the acute toxicity of MDA /have been shown/. Rabbits given 500 mg/kg survived with liver and kidney damage while dogs and cats displayed both liver and kidney damage after a single oral dose of 100 mg/kg. Further, in cats blindness could be produced by a single dose as low as 25 mg/kg, liver damage as low as 10 mg/kg. American Conference of Governmental Industrial Hygienists. Documentation of the TLV's and BEI's with Other World Wide Occupational Exposure Values. CD-ROM Cincinnati, OH 45240-1634 2007.
from HSDB /LABORATORY ANIMALS: Acute Exposure/ The acute hepatotoxicity of orally administered MDA was characterized in rats, indicating dose-and time-related toxicity classed as multifocal, cholangiolitic hepatitis, the lesions of which are distributed in portal and mid-zonal regions of liver lobules. Male Sprague-Dawley rats were fasted for 24 hours before and after receiving several doses within 25-225 mg/kg body weight (2 mL/kg volume each). At 24 hours after treatment the common bile duct was cannulated, and bile was collected for 30 mm. The rats were then ensanguined and blood collected. Oral administration of the substance caused a dose-dependent change in all markers of liver injury: The threshold for toxicity was between 25 and 75 mg/kg substance. Methylene dianiline caused concomitant changes in all markers of liver injury measured, including serum ALT, bile flow, serum bilirubin concentration, GGT activity, and liver weight. Liver sections from animals that received a dose of 100 mg/kg had multifocal lesions consisting of hepatocellular necrosis with hemorrhage and moderate neutrophil infiltration. The necrosis involved segments of periportal hepatocytes but did not surround portal tracts. Frequently, the parenchymal insult extended into the mid-zonal regions of hepatic lobules. The lesions associated with the portal triad consisted of bile neutrophil infiltration. A segmental necrotizing vasculitis of the portal vein was also evident. The earliest change identified with the hepatotoxicity of methylene dianiline was bile ductular necrosis, and histologic markers of liver injury continued to increase in severity over the course of 16 hours. Histologic analysis of livers from animals receiving corn oil vehicle demonstrated normal hepatic histology with no apparent lesions. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /LABORATORY ANIMALS: Acute Exposure/ ... No mortalities were caused by a 4-hour single dose of 0.837 mg/L applied to 18 rats, exposing only the snouts and nostrils to a dust containing 66% particles at /less than/ 7 micron. The rats showed exophthalmus, tremors, curved hunched body position, and ruffled fur, but recovered within 2 days. In an inhalation risk test 3 rats were subjected to an atmosphere saturated with MDA by heating a bath of the compound to 200 deg C; all rats survived, showing moderate congestion of lungs and testes at necropsy. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB
/LABORATORY ANIMALS: Acute Exposure/ /When applied dermally/ 1000 mg/kg of a 50% solution of MDA in dimethylsulfoxide killed 5/10 female rats within 7 days, demonstrating apathy, hyperchromodacryorrhea, and jaundice as clinical signs. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /LABORATORY ANIMALS: Acute Exposure/ No edema and only slight erythema reactions were observed on intact rabbit skin up to 48 hours after patch removal following a 24-hour application of 500 mg moistened MDA under occlusion. Little enhancement of the reaction was seen with application to abraded skin. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /LABORATORY ANIMALS: Acute Exposure/ Only a mild eye reaction was observed in rabbits following instillation of 100 mg MDA into the conjunctival sac. The effects reversed within 3-7 days after instillation of the substance European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /LABORATORY ANIMALS: Acute Exposure/ A single gavage dose of 25 mg/kg (range tested 25-225 mg/kg) increased serum alanine aminotransferase activity and relative liver weight in rats. Higher single doses (50-250 mg/kg) induced cholestasis, biliary epithelial injury, bile duct necrosis, and periportal hepatocellular necrosis. The earliest change identified was bile ductular necrosis 4 hours after dosing. These single dose studies demonstrated that 4,4'-methylenedianiline is selectively toxic to bile duct in rats and that hepatic lesions appear after the lesions to the bile ducts. The minimal effective dose of 25 mg/kg from /one/ study is considered a minimal LOAEL and is the basis for derivation of an acute oral MRL of 0.2 mg/kg/day. DHHS/ATSDR; Toxicological Profile for Methylenedianiline (PB/99/102568/AS) (August 1998). Available from, as of February 23, 2009: http://www.atsdr.cdc.gov/toxpro2.html#bookmark05
from HSDB /LABORATORY ANIMALS: Acute Exposure/ /A/ study in which NOAELs of 35 mg/kg/day and 58 mg/kg/day were identified in rats and mice, respectively, and the earlier report that established a NOAEL of 8.3 mg/kg/day in rats. This NOAEL, 8.3 mg/kg/day, served as the basis for derivation of an intermediate oral MRL of 0.08 mg/kg/day. Gavage, drinking water, or diet were used as vehicles in the studies, which suggests that the method of administration of 4,4'-methylenedianiline is not a determining factor in liver toxicity. In addition to elevated serum transaminases, the most commonly seen liver alterations were hyperplasia of the bile ducts, fatty infiltration, fibrosis, and atrophy of the liver parenchyma. In general, it appeared that most of the hepatic lesions were at least partially reversible following cessation of treatment. DHHS/ATSDR; Toxicological Profile for Methylenedianiline (PB/99/102568/AS) (August 1998). Available from, as of February 23, 2009: http://www.atsdr.cdc.gov/toxpro2.html#bookmark05
from HSDB /LABORATORY ANIMALS: Acute Exposure/ The potential of MDA to produce delayed contact hypersensitivity in guinea pig was evaluated with the Guinea Pig Maximisation Test. The study was performed with 15 animals per group and using a 5% concentration at each induction phase and a 2% concentration at challenge, 3/15 (20%, mild) of the test group animals showed a skin reaction to MDA at challenge. The test concentrations used were selected on the basis of the systemic toxicity of MDA. Results from a guinea pig skin hypersensitization test, a slightly modified version of the Landsteiner-Draize technique, were considered to be positive on the basis of the increase of size and redness around the site of the injections in the test group. In this non validated test a total of 10 intradermal injections were made during the induction phase followed by one intradermal injection two weeks later during challenge. The concentration was 0.1% MDA in polyethyleneglycol. Ten animals were used in each the treated and control group. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /LABORATORY ANIMALS: Acute Exposure/ A study /was/ conducted using a "repeated insult" technique ... involving nine topical applications of 1% MDA in Dowanol SOB during the induction phase and of a "challenge"-dose. When tested on the skin of guinea pigs using a "repeated insult" technique, MDA did not cause a sensitization reaction in any of the nine test animals. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /LABORATORY ANIMALS: Acute Exposure/ In order to evaluate the DNA-binding capacity of MDA, radiolabeled ((3)H)MDA was administered intraperitoneally to groups of 6 male Wistar rats at single doses of 5.6 and 116.5 umol/kg (corresponding to 11 and 23.1 mg/kg;). In the liver relatively low covalent binding indices of 1.05 (low dose) and 2.3 (high dose) were determined [CBI = (umol of MDA bound / mol of DNA) / (mmol of MDA applied / kg bodyweight)]. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /LABORATORY ANIMALS: Acute Exposure/ Cats and dogs appear to be more sensitive than rats to the effects of single oral exposure to MDA. In briefly reported studies, 1/3 cats died after oral application of 25 mg/kg body weight and 1/3 dogs died after application of 50 mg/kg body weight MDA. Liver and kidney damage was noted at 10 mg/kg and above, and doses of 25-100 mg/kg produced blindness due to retinal atrophy in cats. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /LABORATORY ANIMALS: Acute Exposure/ /It/ ... has been found to cause blindness in cats. ...A single near-lethal dose of 100 mg/kg produced selective atrophy of rods, cones, and nuclei in outer granular layer. Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 312
from HSDB /LABORATORY ANIMALS: Acute Exposure/ Female Wistar rats were used in a study of the binding of 4,4'-methylenedianiline to rat hemoglobin. Rats were injected intraperitoneally with 4,4'methylenedianiline in dose ranges of 1 to 100 mg/kg or with (14)C labeled 4,4'-methylenedianiline at 1 mg/kg; rats were similarly treated with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea at 1 to 5 mg/kg. One analytical technique involved degradation of the isolated hemoglobin adduct by a modified Edman technique to release 4,4'-methylenedianiline modified N-(2-hydroxyethyl)valine, which was analyzed, using a combination of gas chromatography mass spectrometry with selected ion recording, as the trimethylsilyl-ether derivative of the N-(2-hydroxyethyl)valine pentafluorophenylhydantoin adduct. Another analytical technique involved hydrolysis of the isolated hemoglobin adduct with weak acid or alkali to release 4,4'-methylenedianiline, which was analyzed, using a combination of gas chromatography mass spectrometry with selected ion recording, as a heptafluorobutyryl derivative. Comments were included on the biotransformation of carcinogenic aromatic amines. The sulfinic acid amide was considered to be one ot the major hemoglobin adducts with 4,4'-methylenedianiline, and a method was developed for quantifying this adduct in rat hemoglobin. A linear relationship was established between 4,4'-methylenedianiline dose and the amount of adduct cleaved from hemoglobin. Farmer PB, Bailey E; Archives of Toxicol 13: 83-90 (1989)
from HSDB /LABORATORY ANIMALS: Acute Exposure/ Methylenedianiline (DAPM) is considered a cholangiodestructive toxicant in vivo. Increases in biliary inorganic phosphate (P(i)) and glucose occur prior to biliary epithelial cell (BEC) injury, which could be due to increased paracellular permeability and/or impairment of P(i) and glucose uptake by BEC. To evaluate these possibilities, /investigators/ induced mild injury [loss of BEC from major bile ducts (6 hr), ultrastructural alterations in BEC mitochondria and Golgi cisternae (3 hr), and striking increases in biliary P(i) and glucose (3-6 hr)] with 25 mg DAPM/kg and then assessed temporal alterations in tight junction (TJ) permeability by measuring bile to plasma (B:P) ratios of [(3)H]-inulin. Parameters maintained by hepatocytes in bile were unchanged (bile flow, bile salts, bilirubin) or only transiently perturbed (protein, glutathione). Minimal elevations in B:P ratios of inulin occurred temporally later (4 hr) in DAPM-treated rats than increases in biliary P(i) and glucose. To confirm a direct effect of DAPM on BEC TJs, we measured transepithelial resistance (TER) and bi-ionic potentials of BEC monolayers prior to and after exposure to pooled (4-6) bile samples collected from untreated rats (Basal Bile) or rats treated with 50 mg DAPM/kg (DAPM-Bile). BEC TJs were found to be cation selective. Exposure to DAPM-Bile for 1 hr decreased TERs by approximately 35% and decreased charge selectivity of BEC TJs while exposure to Basal Bile had no effects. These observations indicate that DAPM-Bile impairs paracellular permeability of BEC in vitro. ...[Santa Cruz, V et al; - Toxicology Letters 169 (1): 13-25 (2007)] Full text: PMC1866304 Abstract: PubMed from HSDB /LABORATORY ANIMALS: Acute Exposure/ ...Rapid acetylator F344 rat liver cytosols catalyzed the N-acetylation of MDA at significantly higher rates than those from slow acetylator WistarKyoto (WKY) inbred rats. To test the effect of NAT2 genetic polymorphism on hepatotoxicity from acute MDA exposure, /investigators/ compared hepatotoxicity in rapid (F344) and slow (WKY) Nat2 acetylator inbred rats that were administered MDA. Based on the results of dose-response studies ranging up to 150 mg/kg MDA administered by intragastric gavage, the effect of a moderately hepatotoxic dose (37.5 mg/kg) was compared in rapid versus slow acetylator rats. Plasma alanine transaminase enzyme activities were approximately 5-fold higher (p < 0.05) in rapid versus slow acetylator rats after MDA treatment, and necrotizing hepatitis with portal damage consisting of bile ductular necrosis, portal expansion, and inflammation was clearly more prominent. These results suggest that acetylator phenotype is an important factor for susceptibility toward MDA hepatotoxicity. Abstract: PubMed Zhang, et al; The Journal of Pharmacology and Experimental Therapeutics 316 (1): 289-294 (2006)
from HSDB /LABORATORY ANIMALS: Acute Exposure/ ... /The goal of this study/ was to determine if gender differences in 4,4'-diaminodiphenylmethane (DAPM) toxicity were due to differences in biliary excretion or covalent binding of DAPM metabolites in the liver. Bile duct-cannulated female and male Sprague-Dawley rats were gavaged with vehicle or with 25 or 50 mg (14C)DAPM/kg, and bile was collected for 6 hr. Serum and bile indicators of hepatobiliary toxicity were assessed, and radioactivity was measured in bile, serum, urine, and liver. At the 25 mg/kg dose, serum parameters were elevated only in female rats, while increases in serum parameters were observed in both genders at the 50 mg/kg dose. In males rats, biliary constituents altered by DAPM [inorganic phosphate (Pi), glucose, gamma-glutamyl transpeptidase (GGT)] showed time- and dose-dependent responses. In female rats, however, biliary constituents showed either minimal dose-response effects (glucose), were increased equivalently at both doses (Pi), or were not altered by DAPM treatment (GGT). At the 50 mg/kg dose, liver alkaline phosphatase decreased in female but not male rats. ... Abstract: PubMed Dugas, TR et al; Journal of Toxicology and Environmental Health. Part A 62 (6): 467-483 (2001)
from HSDB /LABORATORY ANIMALS: Acute Exposure/The effect of 4,4'-methylene dianiline and 4,4'-sulphonyldianiline (dapsone) in vivo on xenobiotic biotransformation in male rat liver was studied. Treatment with 4,4'-methylene-bis(2-chloroaniline) or 4,4'-methylene dianiline but not dapsone caused a dose-dependent increase in ethoxyresorufin O-deethylase activity and a concomitant decrease in aldrin epoxidase activity in male rats. Treatment with 4,4'-methylene-bis(2-chloroaniline) or 4,4'-methylene dianiline resulted in dose-dependent increases in ethoxycoumarin Odeethylation and epoxide hydrolation, while only MOCA induced cystolic glutathione S-transferase activity. Treatment with dapsone resulted in no changes in xenobiotic biotransformation except for the induction of aniline hydroxylation. The results are consistent with the contention that there is a relationship between carcinogenic chemicals and particular alterations in the activities of biotransformation enzymes. Abstract: PubMed Wu K et al; Xenobiotica 19 (11): 1275-83 (1989)
from HSDB /LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ The health hazards from acute inhalation exposure to aerosols were evaluated. Guinea pigs of albino and pigmented strains were exposed nose-only to the aerosols of 4,4'-methylenedianiline in polyethylene glycol 200 solution. The exposure was 4 hr per day, 5 days per week for a total of 10 exposures in 2 weeks. The time-weighted average aerosol concentration was 0.44 +/- 0.09 mg/L and the optical number length mean diameter of the aerosol particle was 2.4 micron with sigma g of 2.1. During exposures, no overt respiratory distress was observed. Two weeks after the exposures, the guinea pigs were tested for possible dermal sensitization by being challenged with a dermal application of 4,4'methylenedianiline polyethylene glycol 200 solutions at concentrations of 0, 2, 20, and 200 mg/mL. Neither dermal irritation nor allergic response was detected under this experimental condition. Thereafter, the animals were tracheostomized for measurements of changes in lung insufflation pressure for detecting possible changes in the distensibility of the lungs from a challenge dose of
an aerosol of 4,4'-methylenedianiline-polyethylene glycol 200 at a concentration of 200 mg/mL. No significant changes were observed under this testing condition. Finally, the animals were euthanized for histopathological examinations of eye, lung, liver, and kidney. The most remarkable findings were the degeneration of the inner and outer segments of the photoreceptor cells and the pigmented epithelial cell layer of the retinas of both albino and pigmented strains of guinea pigs. Abstract: PubMed Leong BK et al; Fundam Appl Toxicol 9 (4): 645-58 (1987)
from HSDB /LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ /Investigators/ reported chronic hepatic cirrhosis in rats within 5 months after seven subcutaneous implantations of about 125 mg of MDA/kg; /Additional investigators/ confirmed the cirrhosis after chronic oral administration of 3 mg MDA/kg and found that oral treatment induced blood dyscrasia. American Conference of Governmental Industrial Hygienists. Documentation of the TLV's and BEI's with Other World Wide Occupational Exposure Values. CD-ROM Cincinnati, OH 45240-1634 2007.
from HSDB /LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ MDA (/greater than/ 99%) was administered in the drinking water for 3 months to 80 male rats and 80 female rats (strain: Tif:RAlf (SPF)) at doses of 0, 80, 400, and 800 ppm (equivalent to approximately 7.5, 23 and 31 mg/kg bw/day in males and 8, 22 and 32 mg/kg bw/day in females). 20 out of 80 animals of each sex and each group were used for a 4-week recovery period ... One high dose female was sacrificed after the 53rd day of treatment with trembling and in an emaciated condition. Rats receiving 400 and 800 ppm MDA showed depressed food consumption, water consumption and body weight gain in males and females during the test period and at the end of the treatment. Water and food uptake normalized during recovery, whereas body weight did not recover in the recovery period. No clinical signs were observed in the low dose groups. Anemia was seen in males and females of the mid and high dose groups at the end of treatment and after recovery. The number of RBC was decreased, the concentrations of hemoglobin and hematocrit were reduced, in response to this MCV, MCH and the number of reticulocytes were elevated. In high dose animals, the number of leukocytes were higher than in control groups, the relative amount of neutrophils increased in high dose males and females at the end of treatment and in males of the mid and high dose groups of the recovery groups. High dose females had lower percentages of lymphocytes at the end of the test period. The prothrombin time was prolonged in high dose males and females of the high dose group. Elevated serum concentrations of alkaline phosphatase, ALAT, ASAT, urea, bilirubin, cholesterol were observed in males and females of the mid and high dose groups at the end of the test period. After recovery the concentrations of alkaline phosphatase, ASAT (males only) and urea remained still elevated. Total proteins had higher concentrations in males of the mid and high dose groups at the end of treatment and afterwards decreased at the end of recovery in males and females of the mid and high dose groups. Levels of potassium were decreased in mid and high dose males at the end of test period and increased in mid and high dose females after recovery. No treatment-related changes were observed in urinalysis. Corresponding to the lower body weight in males and females of the mid and high dose group the absolute weights of several organs were lower than controls at the end of treatment and recovery influencing also the relative organ body or brain ratios. Rats treated with 800 ppm developed a hyperplasia of small biliary ducts with initial fibrosis in the peripheral parts of the liver lobules, a hypertrophy of the thyroid follicular epithelial cells and diffuse hyperplasia of the glandular structures with marked colloid depletion. At the end of the recovery period the liver lesions persisted and the thyroid stimulation was much less pronounced. Only 3/10 males and 2/10 females showed slight stimulation of the follicular epithelium. Rats receiving 400 ppm MDA displayed similar histopathological changes of a less severe nature. After recovery liver lesions persisted, but no thyroid changes were noted. One male rat of the high dose group and one male and one female of the mid dose groups showed a focal nodular hyperplasia of the thyroid. In the 80 ppm group no liver lesions were noted, but a slight stimulation of the follicular epithelium in the thyroids was observed in 2/20 males and 2/20 females. Whereas nephrocalcinosis was evident in all females of treatment and control groups, mineralisation was seen in all males of the mid dose group and in 21 of 3O males of the high dose groups. One male of the 80 ppm group and none of the control males showed kidney mineralisation. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ A study was performed in B6C3F1 mice and F344/N rats receiving MDA as the dihydrochloride in drinking water for 14 days resp. 90 days. In the 14-day study five rats/sex/group received 0, 200, 400, 800, 1600, and 3200 ppm (equivalent to approx. 0, 17.6, 32.8, 36.5, 78.4, 89.2 in male rats, and 0, 16.6, 33.2, 51.2, 80, 128 mg/kg bw/day in female rats, calculated on an assumed water uptake of 1 00 g/kg bw/day, taking into account the drastic reduce of water consume up to 72% in males and 60% in females). Five mice/sex/group received the same MDA concentrations in the drinking water (equivalent to approx. 0, 31.8, 77.6, 135.6, 170.4, 100.8 mg/kg bw/day in male mice, and 0, 29.7, 57, 102, 132, 100.8 mg/kg bw/day in female mice, calculated on an assumed water uptake of 150 g/kg bw/day, taking into account the reduced water consume up to 79% in both sexes). Water consumption was lowered in all dosed rat groups and in male mice that received 1600 ppm or more and in female mice at 800 ppm or higher. Mean body weight gain was depressed dose-related in all rat groups and in mice that received 800 ppm or more. In some rats receiving 1600 or 3200 ppm, crater-like foci with black content in the cardiac part of the stomach were noted. No premature deaths occurred in rats. Survival was reduced in some mice at 800 ppm or higher, all mice died at 3200 ppm. No compound-related lesions were identified in mice at necropsy. Hematology, clinical biochemistry and histopathological examinations were not performed in any species. A NOAEL was not determined in the rat study, whereas in mice the NOAEL was 400 ppm (equiv. to 77.6 mg/kg bw/day in males, resp. 57 mg/kg bw/day in females). European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In a 14-day study 10 male and female Sprague-Dawley rats were treated by gavage with 0, 25 mg and 50 mg/kg bw/day of MDA on 5 days/week. Anemia with decreased numbers of red blood cells and reduced levels of hemoglobin and hematocrit and increased numbers of leukocytes were registered in high dose males and females. In rats of this dose group clinical chemistry revealed an increase of serum enzymes (ALAT, alkaline phosphatase), total proteins (males only), total lipids and total bilirubin. Levels of calcium increased and an organic phosphorus levels were decreased. Low dose animals had only lower values of total lipids and increased concentrations of alkaline phosphatases. High dose males and females showed elevated organ weights (abs/rel) of the liver, kidneys, spleen and thyroid. Mean liver weight was also increased in 25 mg-females. Urinalysis yielded effects in females of both dose groups. Isolated renal cells and cylinder in the urinary sediment were evident. Histopathology showed dose related mild-moderate lesions in both dose groups consisting in proliferation of bile ducts with initial fibrosis and inflammatory reactions of the liver, enlargement of the spleen due to extramedullary hematopoiesis, hyperplasia of the thyroid epithelium. Minimal renal tubular cell desquamation was evident in the kidneys of 3 control males, 4 males and 1 female at 25 mg/kg and 6 males and 1 female at 50 mg/kg. The low dose of 25 mg/kg represented the LOAEL of this study, a NOAEL was not derived. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ The livers of male Wistar rats fed in groups of 3-8 animals/dose with a diet containing 0 or 1000 ppm MDA (/roughly/ 70 mg/kg
bw/day) for 8 weeks (plus recovery of 8, 16, 24, 32 weeks), 16-weeks (plus recovery of 8, 16, and 24 weeks), 24 weeks (with recovery of 8 and 16-weeks), 32-weeks (plus 8 weeks of recovery) or 40 weeks (without recovery) were examined at the end of the treatment and recovery periods. A proliferation of bile ducts, oval cell infiltration, fibrosis and hepatocellular necrosis of the livers were seen. The hepatic parenchyma was replaced by proliferating bile ducts and portal cirrhosis developed. The severity of the lesions gradually increased with the treatment periods and regressed with prolongation of the observation time, but did not achieve complete reversibility. Histopathology revealed a periportal proliferation of bile ducts, oval cell infiltration, focal necrosis and fatty change of hepatocytes and fibrosis. Liver lesions showed a gradual increase from mild severity after 8 weeks of treatment to marked severity with longer treatment duration, the lesions were most prominent at the end of the treatment duration and showed regression during recovery time. At 40 weeks of treatment, the hepatic parenchyma was replaced by proliferating bile ducts and portal cirrhosis. The activity of ASAT was increased in rats at study termination at weeks 8, and 16, levels were normalized within one week of recovery. Only at the end of 8 weeks of treatment higher activities of ALAT and alkaline phosphatase were seen. Increased levels of gamma-glutamyl transpeptidase was observed at the end of all treatment periods, levels showed a tendency to normalization during recovery. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ The effect of inhaled aerosols of MDA in polyethylene glycol 200 (PEG) solution /was investigated/ in male guinea pigs of albino Hartley strain and pigmented guinea pigs of mixed variety. The study was not reliable with respect to toxic effects on the respiratory tract (only few organs were investigated, no histopathology on the upper respiratory tract). Although an effect of MDA (0.44 mg/L) occurred in this 14-day inhalation study (4 hr/day, 5 day/wk) in the eyes of eight exposed animals (the retinas of all animals showed a degeneration of the inner and outer segments of the photoreceptor cells and the pigmented epithelial cell layer, not due to an interaction with melanin). European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ A NOAEL can be derived from the 90-day study which was 11.4 mg/kg bw/day in male mice and 14.4 mg/kg bw/day in female mice. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ A single study in animals indicates that no gross or histopathological lesions were detected in the lungs and trachea of rabbits that received daily skin doses of 12,000 mg 4,4'-methylenedianiline/kg as an aqueous paste for 10 consecutive days. DHHS/ATSDR; Toxicological Profile for Methylenedianiline (PB/99/102568/AS) (August 1998). Available from, as of February 23, 2009: http://www.atsdr.cdc.gov/toxpro2.html#bookmark05
from HSDB /LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ An acute-duration study reported a 71% increase in absolute weight of the uterus in ovariectomized rats administered 110-146 mg 4,4'-methylenedianiline by gavage for 5-14 days. Histopathological examination of the uterus revealed an atypical folliculoid response in the endometrium. DHHS/ATSDR; Toxicological Profile for Methylenedianiline (PB/99/102568/AS) (August 1998). Available from, as of February 23, 2009: http://www.atsdr.cdc.gov/toxpro2.html#bookmark05
from HSDB /LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ .../Investigators/ treated male and female rats with 25 mg 4,4'-Methylenedianiline (DAPM)/kg or vehicle once per week for 17-22 wk. Though concentric fibrosis around bile ducts of the liver was noted, vascular medial hyperplasia was also prominent. Morphometric analysis of histologic sections revealed that in male rats, vessel wall area increased relative to lumen area in hepatic arteries by 22 wk. However, in female rats, wall areas of both hepatic and pulmonary arteries increased relative to lumen area by 17 wk. In both male and female rats, increased wall thickness was localized to the medial layer; no intimal changes were noted. ... Abstract: PubMed Dugas, TR et al; Cardiovascular toxicology 4 (1): 85-96 (2004)
from HSDB /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Sub-chronic (6 wk) & chronic (16 wk) periods of oral admin of 8 mg/kg caused liver damage in rats, with formation of hyperplastic nodules, adenoma like bile duct proliferation & cirrhosis like changes. In 2 animals it caused hemangiomas of the liver. GOHLKE P; Z GESAMTE HYG IHRE GRENZGEB 24 (3): 159 (1978)
from HSDB /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ /P,P'-methylenedianiline was administered to 24 male rats/ ... at near max tolerated dose by gastric intubation in arachis oil 5 days/wk for 121 days (total dose, 3.3 g/kg body wt). ... 19 animals /were/ alive at 12 mo, 17 at 18 mo & 12 at 2 yr. All ... had cirrhosis of liver ... . Two benign hepatomas at 792 and 947 days, as well as a variety of miscellaneous tumors /were found/. IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php , p. V4 82 (1974)
from HSDB /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ ... Intragastric dosing ... /was/ continued for about 18 mo /in rats/ (total dose, 6 g/kg body wt). Two liver tumors, 1 intestinal tumor, 1 pituitary tumor and 2 subcutaneous fibromas were found. ... /Use of other substances demonstrated/ that these rats were susceptible to liver carcinogens. IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php , p. V4 82 (1974)
from HSDB
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Groups of 25 male and 25 female Wistar rats /were injected/ with sc doses of 30-50 mg/kg body weight in physiologic saline at 1 to 3 wk intervals over a period of 700 days (avg total dose, 1.4 g/kg body weight). Mean survival time was 970 days in males and 1060 in ... females, compared with 1007 ... in controls. ... 33 malignant tumors /were/ found in treated rats, compared with ... 16 malignant tumors in /an/ equal number of controls. Four hepatomas were reported in treated rats. Exact incidence of tumor types observed was not recorded. IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php , p. V4 83 (1974)
from HSDB /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ When administered orally to 16 rats in 4-5 doses of 20 mg, 4,4'-diaminodiphenylmethane induced hepatomas & kidney tumors in 1 rat, adenocarcinoma of uterus in another, and liver lesions in most of those treated. SCHOENTAL R; NATURE (LONDON) 219 (5159): 1162 (1968)
from HSDB /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ 4,4'-Methylenedianiline and its dihydrochloride were tested for carcinogenicity by oral administration in mice /and/ rats ... . Treatment-related increases in the incidences of thyroid follicular cell adenomas and hepatocellular neoplasms were observed in both male and female mice. In rats, treatment related increases in the incidences of thyroid follicular cell carcinomas and hepatic nodules were observed in males, and thyroid follicular cell adenomas occurred in females. In a study in rats in which 4,4'methylenedianiline was administered orally in conjunction with a known carcinogen, the incidence of thyroid tumors was greater than that produced by the carcinogen alone. IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php , p. V39 358 (1986)
from HSDB /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ The LOAEL representing the most sensitive adverse (nonneoplastic) effect after repeated oral application was derived /from a study with/ 7.5 mg/kg bw/d in male rats and 8 mg/kg bw/day in female rats. This LOAEL is corresponding to the level of LOAEL from the 2-year study on rats on nonneoplastic effects (9, resp. 10 mg/kg bw/day in male, resp. female rats). Although the studies had not examined parameters of hematology, bioclinical chemistry and urinalysis, the LOAEL of 9 mg/kg bw/day from the long term study was considered to be the most appropriate value for quantitative risk assessment. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In two-year studies in F344 rats and B6C3F1 mice, 150 and 300 ppm MDA administered in drinking water (equiv. to 9 and 16 mg/kg bw/day for male rats and 10, resp. 19 mg/kg bw/day for female rats, 25, resp. 58 mg/kg bw/day for male mice, and 19, resp. 43 mg/kg bw/day for female mice) was clearly carcinogenic, producing thyroid and liver tumors in both species. Survival was comparable among all groups. High dose female rats had lower mean body weights than those of the controls. No consistent effects on body weights were identified in the low dose females or either in dosed group of males. The average daily water consumption per rat by low- and high dose rats was 87% and 75% that of the controls for males and 93% and 82% for females. No compound-related clinical signs were observed. No significant differences in survival were observed between any groups of either sex of rats. In rats, the incidence of thyroid follicular cell carcinoma was significantly higher in high dose males than in controls. High dose female rats showed a significant higher rate of follicular cell adenomas than in the controls. Neoplastic nodules in the liver showed a significantly higher incidence in low and high dose males than in controls. One bile duct adenoma was found in one high dose male rat. Transitional cell papillomas of the urinary bladder were found in 2/50 low dose and 1/50 high dose rats. In mice, the incidences of follicular cell adenomas gained significance in high dose males and females. Hepatocellular carcinomas were significantly higher in males of each dose group and in high dose females. Hepatocellular adenomas occurred with significant higher incidence in high dose females. Cystic and/or hyperplastic follicular thyroid lesions were increased in high dose female rats and mice of each sex. Rats and mice of each dose group showed toxic liver effects. An increased incidence of kidney nephropathy was evident in both dose groups in mice, high dose male rats showed a higher incidence of renal mineralisation. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Spontaneous thyroid tumors in rats were infrequent, incidences 1% for follicular cell adenomas or carcinomas were reported for untreated male and female F344 rats. None of the rat control groups of this study had thyroid follicular tumors except one out of 49 males with a follicular cell adenoma. Also, it is known that B6C3F1 mice have low spontaneous rates of thyroid follicular adenomas (1%) and of follicular carcinomas (0.5%). No tumor was observed in the thyroid of the control mice of the carcinogenicity study on MDA. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Another extremely rare tumor, a bile duct adenoma was observed in 1/50 high dose rat of the NTP cancer study. Although the incidence is very low, the authors discussed a possible association to the MDA treatment. This tumor was not observed in 3633 control rats of this strain in the NTP Bioassay Program and the bile duct hyperplasia may be discussed as the corresponding preneoplasia. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Liver dilation, fatty metamorphosis, and focal cellular change were described in rats treated with 9 mg 4,4'methylenedianiline/kg/day in the drinking water for 103 weeks. In the same study, liver degeneration was seen in mice receiving 25 mg/kg/day. Both dose levels represent the lowest levels tested. DHHS/ATSDR; Toxicological Profile for Methylenedianiline (PB/99/102568/AS) (August 1998). Available from, as of February 23, 2009: http://www.atsdr.cdc.gov/toxpro2.html#bookmark05
from HSDB
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ A high incidence of nephropathy was reported in male and female mice treated with 19-25 mg 4,4'methylenedianiline/kg/day in the drinking water for 103 weeks. Male mice also exhibited renal papilla mineralization at a dose level of 57 mg/kg/day. DHHS/ATSDR; Toxicological Profile for Methylenedianiline (PB/99/102568/AS) (August 1998). Available from, as of February 23, 2009: http://www.atsdr.cdc.gov/toxpro2.html#bookmark05
from HSDB /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Various lesions to the kidney and urinary bladder were observed in 9 dogs treated with approximately 2.7 mg 4,4'methylenedianiline/kg/day, 3 days per week for 54-84 months. Kidney abnormalities included rough surface, congestion, glomerulonephritis, cloudy swelling, and thickening of the basement membrane. Hyperemia in the urinary bladder was noticed in two dogs, whereas mucosal hyperplasia, edema, lymphocytic infiltration, and marked congestion of the urinary bladder were observed in another dog. DHHS/ATSDR; Toxicological Profile for Methylenedianiline (PB/99/102568/AS) (August 1998). Available from, as of February 23, 2009: http://www.atsdr.cdc.gov/toxpro2.html#bookmark05
from HSDB /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ The potential carcinogenicity of 4,4'-methylenedianiline by the dermal route was examined in mice. A solution of the test material in ethanol was applied to the clipped skin of male and female C3Hf/Bd mice 3 times per week for 24 months. Positive controls were treated with benzo[a]pyrene and negative controls with vehicle alone. Estimated doses were 5.3, 10.7, and 21.3 mg 4,4'-methylenedianiline/kg/day. Treatment with 4,4'-methylenedianiline did not produce tumors at the application site, but increased the incidence of hepatic tumors in females in a dose-related manner (11% vehicle control, 22% low-dose, 25% mid-dose, 85% high-dose); however, a statistical analysis of the results was not provided. The incidence of tumors in the spleen, lungs, kidneys, and ovaries/testes did not increase relative to negative controls. According to the investigators, the C3Hf/Bd strain of mice is unusually susceptible to liver tumors and, therefore, the significance of the findings requires further study. Nevertheless, the dose of 5.3 mg 4,4'-methylenedianiline/kg/day is listed as a Cancer Effect Level ... DHHS/ATSDR; Toxicological Profile for Methylenedianiline (PB/99/102568/AS) (August 1998). Available from, as of February 23, 2009: http://www.atsdr.cdc.gov/toxpro2.html#bookmark05
from HSDB /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Doses of /greater then or equal to/ 261 mg 4,4'-methylenedianiline/kg/day administered in the drinking water for 14 days induced crater-like foci in the cardiac portion of the stomach in female rats. The NOAEL for this effect in females was 130 mg/kg/day. No such lesions were seen in males treated with up to 235 mg/kg/day for the same period of time, but lesions were evident at 469 mg/kg/day. Longer-duration studies reported no gross or histopathogical alterations in the salivary glands, esophagus, stomach, pancreas, duodenum, jejunum, ileum, and colon from rats administered up to 141 mg 4,4'-methylenedianiline/kg/day in drinking water for 13 weeks or up to 19 mg/kg/day for 103 weeks. DHHS/ATSDR; Toxicological Profile for Methylenedianiline (PB/99/102568/AS) (August 1998). Available from, as of February 23, 2009: http://www.atsdr.cdc.gov/toxpro2.html#bookmark05
from HSDB /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ A group of five female pure-bred beagle dogs, five to six months of age, received oral administrations of 70 mg 4,4'methylenedianiline ('highly purified', dissolved in corn oil and placed in gelatinous capsules) thrice weekly. A further four female beagles received capsules containing 'crude' 4,4'methylenedianiline (50% 4,4'-methylenedianiline; 50% higher molecular weight analogues). Total doses were 5.0-6.26 g/kg bw 'pure' 4,4'- methylenedianiline over periods of four-and-a-half to seven years, at which time there was one survivor, and 4.0-6.25 g/kg bw 'crude' 4,4'-methylenedianiline over periods of four to seven years, at which time there were two survivors. No tumour of the urinary bladder or liver was found. IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php , p. V39 354 (1986)
from HSDB /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In a study to investigate the possible promoting activity of 4,4'-methylenedianiline on the development of thyroid tumors in rats treated with N-bis(2-hydroxypropyl)- nitrosamine (DHPN), a group of 21 male inbred W rats, seven weeks old, received a single intraperitoneal injection of 2800 mg/kg bw DHPN [purity unspecified] and were maintained on a diet containing 1000 mg/kg 4,4'-methylenedianiline [purity unspecified] for 19 weeks. A second group of 21 males were fed a diet containing 1000 mg/kg of diet 4,4'-methylenedianiline. Groups of 21 rats each received a single intraperitoneal injection of either 2800 mg bw DHPN (positive controls) or 0.5 mL saline/100 g bw (negative controls), followed by basal diet for 19 weeks. All animals were still alive at the termination of the experiment. There was a significant (p < 0.05) increase in the incidence of thyroid tumors (polymorphofollicular, microfollicular and papillary adenomas, and follicular carcinomas) in the rats treated with DHPN plus 4,4'-methylenedianiline (19/21) over that in the group treated with DHPN alone (6/21). IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php , p. V39 355 (1986)
from HSDB /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ 4,4'-Methylenedianiline produced toxic effects in the liver (enlargement) and bile duct when administered to rats by gavage. Hepatotoxic effects seen in rats administered 4,4'- methylenedianiline by gavage daily for ten days included necrotizing cholangitis with 8-600 mg/kg bw and periportal necrosis and glycogen loss with 200 mg/kg bw or more; marked mitotic activity was observed in hepatocytes and bile duct epithelium. Atrophy of liver parenchyma was observed in Wistar rats given 83 mg/kg bw per day for 12 weeks. Cirrhosis occurred in all of 21 male rats administered an average dose of 38 mg/kg bw 4,4'-methylenedianiline by gavage on five days per week for 17 weeks. Administration to rats of 1000 mg/kg 4,4'-methylenedianiline in the diet for 12 weeks caused severe bile-duct proliferation with concurrent oval-cell and inflammatory cell infiltration, fibrosis and dilatation of smooth endoplasmic reticulum. Bile-duct hyperplasia was found in all male and female rats that received 800 mg/L 4,4'-methylenedianiline dihydrochloride in the drinking-water for 13 weeks and in approximately one-third of those receiving 400 mg/L under similar conditions. Bile-duct proliferation occurred in male rats fed a diet containing 1000 mg/kg 4,4'-methylenedianiline for 40 weeks. The hepatic parenchyma was replaced by proliferating bile ducts, and eventually portal cirrhosis developed. These alterations were reversed when treatment was discontinued. Bile-duct proliferation was also observed in rats receiving an oral dose of 20 mg/kg bw 4,4'-methylenedianiline per day for 16 weeks. IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php , p. V39 356 (1986)
from HSDB
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Groups of eight male and eight female rats [strain and age unspecified] received four or five doses of 20 mg/rat 4,4'methylenedianiline [purity not stated] by gastric intubation over a period of less than eight months and were observed until death. One hepatoma and a haemangioma-like tumour of the kidney were found in a male rat after 18 months. An adenocarcinoma of the uterus was found in one female after 24 months. Most animals had varying degrees of liver fibrosis and inflammation. IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php , p. V39 354 (1986)
from HSDB /LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ No gross or histopathogical alterations were observed in the ovaries, uterus, mammary glands, seminal vesicles, prostate, or testes of rats administered up to 141 mg 4,4'-methylenedianiline/kg/day in drinking water for 13 weeks or up to 19 mg/kg/day for 103 weeks DHHS/ATSDR; Toxicological Profile for Methylenedianiline (PB/99/102568/AS) (August 1998). Available from, as of February 23, 2009: http://www.atsdr.cdc.gov/toxpro2.html#bookmark05
from HSDB /LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In /one/ study, fetuses from pregnant rats treated by gavage with 37 mg 4,4'-methylenedianiline/kg/day (as the chlorohydrate) on gestation days 14-20 had liver alterations in the form of fatty infiltration of the parenchyma. This dose level also caused histological alterations in the livers from the dams. DHHS/ATSDR; Toxicological Profile for Methylenedianiline (PB/99/102568/AS) (August 1998). Available from, as of February 23, 2009: http://www.atsdr.cdc.gov/toxpro2.html#bookmark05
from HSDB /LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Fetuses from 1 of 5 dams administered 219 mg 4,4'-methylenedianiline/ kg/day on gestation days 7-20 showed delayed closing of the calvaria, enlarged tongue, and an abnormally large snout. The 219 mg/kg/day dose level was lethal to 1 of 5 pregnant rats. DHHS/ATSDR; Toxicological Profile for Methylenedianiline (PB/99/102568/AS) (August 1998). Available from, as of February 23, 2009: http://www.atsdr.cdc.gov/toxpro2.html#bookmark05
from HSDB /LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Female Wistar rats were administered 4,4' diaminodiphenylmethane by gavage at 75 mg/day, and 12 mg/day for 21 days. Hepatic lesions were observed in the mothers, and in some cases there were macroscopic, and microscopic, hepatic lesions in the fetus. At the higher dose there were sometimes neural tube defects without hepatic lesions. European Commission, ESIS; IUCLID Dataset, 4,4-Diaminodiphenylmethane (101-77-9) p 135 (2000 CD-ROM edition). Available from, as of March, 5 2009: http://esis.jrc.ec.europa.eu/
from HSDB /LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ /Around hatching time/ a hole was drilled through the shell and into the air cell /of Leghorn hens/. /0.05 mL of 10% MDA in ethanol/ ... was injected into the yolk, using the hole in the shell, and the hole was covered with clear adhesive tape ... There was a 95% hatch with the control eggs receiving ethanol. There was a reduced hatch of 30% with the eggs receiving MDA in ethanol. More than 90% of the chicks hatched after administration of MDA had a short mandible, and leg damage consisting of a severe bending of the tibia and a general shortening of the leg bones. MDA at 5 mg/egg was said to be extremely teratogenic. European Commission, ESIS; IUCLID Dataset, 4,4-Diaminodiphenylmethane (101-77-9) p 138 (2000 CD-ROM edition). Available from, as of March, 5 2009: http://esis.jrc.ec.europa.eu/
from HSDB /GENOTOXICITY/ The DNA repair test in rat hepatocytes was used to examine the genotoxicity of nine chemicals which are used industrially as epoxy resin hardeners. Clearly positive DNA repair responses were elicited by seven of the chemicals, including 4,4'-diaminodiphenylmethane. It is suggested that further studies be made on 4,4-diaminodiphenylmethane which demonstrated a positive response with a high level of unscheduled DNA synthesis in the DNA repair test. Abstract: PubMed Mori H et al; Mutat Res 204(4): 683-8 (1988)
from HSDB /GENOTOXICITY/ With S-9 mix, bacterial mutation tests were positive in a dose-dependent manner in Salmonella typhimurium strains TA100 and TA98 in doses ranging from 3.0 to 333 ug/plate or in doses from 30 ug/plate upwards. Without S-9 mix, negative results were observed in both studies. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /GENOTOXICITY/ A chromosomal aberration test with CHO cells was positive with S-9 mix and equivocal without. With S-9 mix, 3 experiments were performed with 2 hr exposure and 13.5 hr to 15.0 hr sampling; in the dose range 500 to 1000 ug/mL aberration frequencies ranging from 14.0% to 85.0% were induced. Without S-9 mix, 2 experiments were performed with 2 hr exposure and 15 hr or 18 hr sampling; one trial was negative for doses up to 500 ug/mL; in the second trial doses up to 600 ug/mL were negative and an increased aberration frequency of 15% was found for the highest tested dose of 800 ug/mL. Since cytotoxicity data are lacking, the findings cannot be interpreted adequately. It seems that clastogenic effects were limited to doses with strong cytotoxic effects. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /GENOTOXICITY/ In a mouse lymphoma assay which was done only without metabolic activation a weak positive result was obtained. Three experiments were performed; in 2 of them 2- to 3fold increases of mutant frequencies were induced by the highest tested doses of 500 ug/mL or 700 ug/mL; 1000 ug/mL were totally cytotoxic. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB
/GENOTOXICITY/ A test for induction of sister chromatid exchanges (SCE) was marginally positive with and without S-9 mix; data on cytotoxicity were not given. With S-9 mix, one experiment was performed with 2 hr exposure and 24 hr sampling; in doses ranging from 160 to 1600 ug/mL marginal increases of SCE frequencies were found; the maximum effect was 1.3-fold as compared to the negative control. Without S-9 mix, two experiments were performed with 2 hr exposure; in the first experiment with 24 hr sampling, for doses ranging from 16 to 160 ug/mL marginal increases of SCE frequencies were found, the maximum effect was 1.4-fold as compared to the negative control; in a second experiment prolonged sampling times were included, again marginal increases of SCE frequencies were found. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /GENOTOXICITY/ Tests for induction of DNA excision-repair (unscheduled DNA synthesis, UDS) in primary rat hepatocytes led to controversial findings, although - with the exception of rat strains - similar experimental conditions were used with an autoradiographic methodology and analysis of net nuclear grains. /It was / reported on a clear and dose-dependent effect for doses ranging from 1.0 to 100 umol/L (19.8 to 19800 ug/mL) with hepatocytes from male ACI/N rats; a dose of 1000 umol/L was totally cytotoxic... there was no effect with hepatocytes from SpragueDawley rats for doses up 100 ug/mL; higher doses could not be analyzed due to toxicity. With hepatocytes from rats which were induced by Aroclor or phenobarbitone very weak effects European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /GENOTOXICITY/ In two bone marrow experiments with 5 male B6C3F1 mice per group, 3 daily doses of 9.3, 18.5 or 37.0 mg/kg led to increased micronucleus frequencies which were less than 2-fold (0.23 to 0.3 5%) as compared to concurrent negative controls (0.17 and 0.19%). Micronucleus frequencies in treated animals were within the range of negative control values obtained for the 49 chemicals which were tested in the described investigation. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /GENOTOXICITY/ In vivo UPS tests with liver cells from male Fischer-344 rats or B6C3F1 mice were negative. Oral doses (gavage) up to the LD50 range were used (rats, 20, 80, 350 mg/kg; mice, 50, 200, 500, 1000 mg/kg); sampling times were 2 and 12 hr after treatment. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /GENOTOXICITY/ In an in vivo bone marrow SCE test with male Swiss mice marginally increases in SCE frequencies were obtained after intraperitoneal administration of 9 and 18 mg/kg. The maximum SCE frequency was 1.4-fold as compared to the concurrent negative control group. The investigation suffers from methodological insufficiencies (only 3 animals with 15 to 20 analyzed cells per group, no toxicity data) and the 'effect' might well be unspecific. European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /GENOTOXICITY/ An in vivo alkaline elution assay with liver DNA from Sprague-Dawley rats led to a positive result. Single intraperitoneal administrations of the LD50 dose 74 mg/kg (0.37 mmollkg) induced clear increases in DNA fragmentation 4 hr and 24 hr after treatment. Since elution was run under pH 12.3, primarily single and double strand breaks in DNA were detected (not alkali-labile sites). European Chemicals Bureau; European Union Risk Assessment Report, 4,4-METHYLENEDIANILINE (101-77-9) (2001). Available from, as of February 19, 2009: http://esis.jrc.ec.europa.eu/
from HSDB /GENOTOXICITY/ 4,4'-Methylenedianiline also was shown to be mutagenic in the eukaryotic organism Saccharomyces cerevisiae with and without metabolic activation. DHHS/ATSDR; Toxicological Profile for Methylenedianiline (PB/99/102568/AS) (August 1998). Available from, as of February 23, 2009: http://www.atsdr.cdc.gov/toxpro2.html#bookmark05
from HSDB /GENOTOXICITY/ ...Diisocyanates are reactive compounds, MDI can react under physiological conditions with various functional groups found on biological molecules resulting in conjugate formation or undergo non-enzymatic hydrolysis to form 4,4'-methylenedianiline (MDA). /Investigators/ have previously reported that addition of MDI directly to Chinese hamster lung fibroblasts (V79) cultures did not induce micronuclei (MN), but MDA, and the glutathione and cysteine conjugates of MDI (BisGS-MDI and BisCYS-MDI), induced a concentration-dependent increase in the frequency of MN. The conventional MN assay does not discriminate between MN produced by acentric chromosome fragments from those arising due to whole lagging chromosomes that were not incorporated into daughter nuclei at the time of cell division. The mechanism of MN induction from these potential MDI metabolites/reaction products was explored in the present study using immunofluorescent staining of kinetochore in MN of cytokinesis-blocked V79 cells. This assay discerns the presence of centromere within the MN to distinguish the MN containing centric chromosomes from those containing acentric fragments. Eighty five percent of MDA-induced MN were negative with respect to anti-kinetochore antibody binding (KC(-)). This is consistent with an interaction between MDA and DNA resulting in chromosome breakage. However, BisGS-MDI and BisCYS-MDI induced a higher percentage of MN that were positively stained by the antikinetochore antibody (KC(+)). ... Abstract: PubMed Zhong, BZ et al; Mutation Research 497 (1-2): 29-37 (2001)
from HSDB /GENOTOXICITY/ ...4, 4'-Methylenedianiline, a carcinogen which does not induce kidney tumors in rats, gave negative responses in both (Comet assay, micronuclei frequency) in vitro and in vivo assays. These findings give evidence that kidney carcinogens may be identified by short-term genotoxicity assays using as target kidney cells and show that the five chemicals tested produce in primary cultures of kidney cells from human donors effects similar to those observed in rats. Abstract: PubMed Robbiano, L et al; Toxicology and Applied Pharmacology 161 (2): 153-159 (1999)
from HSDB /GENOTOXICITY/ 4,4'-Methylenedianiline (MDA), an aromatic amine used in various industrial processes and previously found to induce tumor development in liver and thyroid of mice and rats, was evaluated for its DNA-damaging activity in primary cultures of hepatocytes and thyreocytes from rat and human donors. After exposure for 4 and 20 hr to MDA concentrations ranging from 10 to 180 microM, a statistically significant increase in the frequency of DNA lesions was revealed by the Comet assay in primary hepatocytes and thyreocytes from donors of both species, the response being dose dependent up to 56-100 microM MDA. DNA fragmentation was more marked after 4 than after 20 hr exposure in all four cell types. DNA was damaged to a lesser extent in human hepatocytes and thyreocytes than in corresponding rat cells and in both species in hepatocytes than in thyreocytes. In both rat and human hepatocytes a 20-hr exposure to the same MDA concentrations elicited a modest amount of DNA repair synthesis, as evaluated by autoradiography. Evidence of a partial reduction of DNA damage, and therefore of only partial DNA repair, was observed in rat hepatocytes and in rat and human thyreocytes incubated for 16 hr in MDA-free medium after a 4-hr MDA treatment. A 4-hr exposure to 56, 100, and 180 microM MDA did not induce DNA lesions in primary cultures of cells from three rat organs, kidney, urinary bladder mucosa, and brain, which are resistant to MDA carcinogenic activity. Under the same experimental conditions any evidence of DNA damage was absent in primary kidney and urinary bladder cells from human donors. Abstract: PubMed Martelli, A et al; Toxicology and applied pharmacology 182 (3): 219-225 (2002)
from HSDB /ALTERNATIVE and IN VITRO TESTS/ ...In vitro treatment of vascular smooth muscle cells (VSMC) with 25-100 microM DAPM resulted in increased DNA synthesis and VSMC proliferation. To test whether the observed alterations in cell cycle control involved VSMC-mediated metabolism of DAPM to electrophilic intermediates, cells were treated with DAPM or DAPM plus 50 microM Nacetylcysteine (NAC). Coincubation with NAC afforded dramatic protection against DAPM-induced VSMC proliferation. Though DAPM had no appreciable effect on levels of reduced glutathione, oxidized glutathione, or oxidant production, DAPM increased glutathione-S-transferase activity in VSMC. These data indicate that DAPM can initiate VSMC proliferation, possibly via VSMCmediated metabolism of DAPM to reactive intermediates. Abstract: PubMed Dugas, TR et al; Cardiovascular toxicology 4 (1): 85-96 (2004)
from HSDB /ALTERNATIVE and IN VITRO TESTS/ Methylenedianiline (DAPM) rapidly injures biliary epithelial cells (BEC) in vivo. Prior to evident BEC injury, biliary glucose and inorganic phosphate appreciably rise, which could stem from loosened tight junctions (TJ). Concurrently, ultrastructural abnormalities in BEC mitochondria of DAPM-treated animals are observed, suggesting other impairments. /The/ objective was to develop an in vitro BEC model to assess the time course of impairments in TJ integrity, glucose uptake, and mitochondrial function following DAPM exposure. /Investigators/ exposed monolayers of primary, polarized rat BEC to bile collected from rats prior to (Basal Bile) or after oral treatment (DAPM-Bile) with 50 mg DAPM/kg. DAPM-Bile collected during 0-60 min (1st hr) and during 61-120 min (2nd hr) after treatment was pooled from four to six rats. When monolayers were exposed to 1st hr DAPM-Bile for 120 min, metabolic activity (XTT assay) decreased approximately 75%, and transepithelial resistance decreased approximately 16% in agreement with an approximately 65% increase in leakage of a glucose analog, methyl-alpha-D-glucopyranoside (AMG), from apical to basolateral media. By 60 min, AMG uptake was decreased approximately 40%. Mitochondrial function was very rapidly compromised, with approximately 120% increases in the green-to-red fluorescence ratio of JC-1 (mitochondrial membrane potential dye) at 15 min and approximately 55% decreases in ATP levels at 30 min. This sequence of events indicates that DAPM impairs BEC mitochondria prior to impairments in glucose uptake or TJ integrity. ... Abstract: PubMed Santa Cruz, V et al; Toxicological Sciences 84 (1): 129-138 (2005)
from HSDB /ALTERNATIVE and IN VITRO TESTS/ ...Liver DNA was obtained from rats treated with radiolabeled MDA (1.11 and 116.5 mumol/kg body weight). The total radioactivity bound to the DNA corresponded to 0.06 and 2.7 adducts per 10(7) nucleotides [covalent binding index (CBI = (mumol of adduct per mol of nucleotide)/(mmol of compound per kg body weight)) of 1.05 and 2.3]. This DNA-binding potency is in the range of weakly genotoxic compounds. The liver DNA was analyzed for the presence of the synthesized adducts by the following methods: (I) HPLC analysis of nucleotides and purines after enzymatic and acid hydrolysis, and (II) 32P-postlabeling after enzymatic hydrolysis. The major adducts found in vivo did not correspond to the synthesized standards. Further work was carried out to determine the structure of the unidentified adducts. It was possible to release MDA and MDA-d4 from DNA of rats dosed with MDA and/or MDA-d4 and from the synthesized adducts using strong base hydrolysis. Liver of two female Wistar rats given 500 mumol/kg MDA-2HCl was hydrolyzed in 0.1 M NaOH overnight at 110 degrees C. GC-MS analysis of the heptafluorobutyric anhydride derivatized dichloromethane extracts detected 428 +/- 40 fmol of MDA/mg of DNA. In the control animals no MDA was found. The experiment was repeated with livers from animals dosed 500 mumol/kg MDA-d4.2DCl. In these rats 488 +/- 19 fmol MDA-d4 was found to be bound at liver DNA. Taking into account a 68% yield of the method, the CBI found in these cases was 0.82 and 1.0, respectively. Abstract: PubMed Schutze, D et al; Chemical research in toxicology 9 (7): 1103-1112 (1996)
from HSDB /IMMUNOTOXICITY/ In some rats, approximately 50% of the thymus cortex was necrotic 24 hours after dosing. However, no histopathological alterations were observed in the spleen. DHHS/ATSDR; Toxicological Profile for Methylenedianiline (PB/99/102568/AS) (August 1998). Available from, as of February 23, 2009: http://www.atsdr.cdc.gov/toxpro2.html#bookmark05
from HSDB Methylenedianiline (DAPM) initially injures epithelial cells of major bile ducts, which is followed by cholestasis, cholangitis, and hepatocellular damage. This pattern of biliary injury resembles that produced by alpha-naphthylisothiocyanate (ANIT), a classic bile duct toxicant. /The authors/ goal was to determine whether prior depletion of hepatic total glutathione (GSx), a condition reported to protect against biliary tract injury by ANIT, would also protect against DAPM-induced bile duct injury. A new protocol for extensive, sustained depletion of GSx was established. /Investigators/ found that administration of 1-bromoheptane followed 1 h later by buthionine sulfoximine resulted in an approximately 96% depletion of hepatic GSx that persisted through 6 h without biochemical or morphological signs of hepatic injury. Treatment of rats with a minimally hepatotoxic dose of DAPM (without GSx depletion) produced at 6 h injury similar to previous studies: moderate oncosis of biliary epithelial cells (BEC), mild edema of portal triads, and increases in glutathione S-transferase (GST) activities without alterations in hepatic GSx/glutathione disulfide (GSSG), coenzyme A (CoASH)/coenzyme A-glutathione disulfide (CoASSG), or thiobarbituric acid-reactive substances (TBARS). In contrast, DAPM treatment of GSx-depleted rats produced severe oncosis of BEC, marked inflammatory and edematous alterations to portal tracts, and oncosis/apoptosis in scattered hepatocytes. The observed acceleration and enhancement of DAPM-induced
liver injury by GSx depletion was associated with a concurrent sevenfold increase in hepatic CoASSG and a fourfold decrease in the ratio of CoASH to CoASSG, compounds presumably localized to mitochondria and a purported index of mitochondrial thiol/disulfide status. These results indicate that: (1) GSx depletion exacerbates BEC and hepatocellular injury induced by DAPM, and (2) the mechanism by which DAPM causes liver injury is likely different from that of the classic bile duct toxicant, ANIT. Abstract: PubMed Kanz, MF et al; Toxicological Sciences 74 (2): 447-456 (2003)
from HSDB
12.1.19 Non-Human Toxicity Values LD50 Dog oral 300 ppm American Conference of Governmental Industrial Hygienists. Documentation of the TLV's and BEI's with Other World Wide Occupational Exposure Values. CD-ROM Cincinnati, OH 45240-1634 2007.
from HSDB LD50 Rat oral 120-250 mg/kg Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983., p. 454
from HSDB LD50 Rat intraperitoneal 193 mg/kg Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2436
from HSDB LD50 Rat subcutaneous 200 mg/kg Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2436
from HSDB LD50 Mouse oral 745 mg/kg Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2436
from HSDB LD50 Mouse intraperitoneal 74 mg/kg Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2436
from HSDB LD50 Rabbit oral 620 mg/kg Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2436
from HSDB LD50 Guinea pig oral 260 mg/kg Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2436
from HSDB LD50 Rat dermal /greater than/ 2500 mg/kg bw. European Commission, ESIS; IUCLID Dataset, 4,4-Diaminodiphenylmethane (101-77-9) p 54 (2000 CD-ROM edition). Available from, as of March, 5 2009: http://esis.jrc.ec.europa.eu/
from HSDB LD50 Mouse subcutaneous /greater than/ 100 mg/kg bw. European Commission, ESIS; IUCLID Dataset, 4,4-Diaminodiphenylmethane (101-77-9) p 67 (2000 CD-ROM edition). Available from, as of March, 5 2009: http://esis.jrc.ec.europa.eu/
from HSDB
12.1.20 Ecotoxicity Values LC50; Species: Agelaius phoeniceus (Red-winged blackbird); Concentration: 148 mg/kg bw /Conditions of bioassay not specified in source examined/ European Chemicals Bureau; European Union Risk Assessment Report, 4,4-Methylenedianiline (101-77-9) p. 22 (2001). Available from, as of February 26, 2009: http://esis.jrc.ec.europa.eu/
from HSDB LC50; Species: Eisenia fetida (Earthworm); Concentration: 444.0 mg/kg dry weight soil for 14 days /Conditions of bioassay not specified in source examined/
European Chemicals Bureau; European Union Risk Assessment Report, 4,4-Methylenedianiline (101-77-9) p. 23 (2001). Available from, as of February 26, 2009: http://esis.jrc.ec.europa.eu/
from HSDB EC50; Species: Moina macrocopa (Daphnid); Conditions: static, nominal concentration); Concentration: 2.3 mg/L for 24 hr; Effect: immobilization /extra pure/ European Chemicals Bureau; European Union Risk Assessment Report, 4,4-Methylenedianiline (101-77-9) p. 20 (2001). Available from, as of February 26, 2009: http://esis.jrc.ec.europa.eu/
from HSDB EC50; Species: Scenedesmus subspicatus (Green algae); Concentration: 21 mg/L for 72 hr; Effect: growth inhibition /95.5-98% purity/ /Conditions of bioassay not specified in source examined/ European Chemicals Bureau; European Union Risk Assessment Report, 4,4-Methylenedianiline (101-77-9) p. 20 (2001). Available from, as of February 26, 2009: http://esis.jrc.ec.europa.eu/
from HSDB EC50; Species: Scenedesmus subspicatus (Green algae); Concentration: 9.8 mg/L for 72 hr; Effect: biomass /technical grade MDA/ /Conditions of bioassay not specified in source examined/ European Chemicals Bureau; European Union Risk Assessment Report, 4,4-Methylenedianiline (101-77-9) p. 22 (2001). Available from, as of February 26, 2009: http://esis.jrc.ec.europa.eu/
from HSDB EC50; Species: Scenedesmus subspicatus (Green algae); Concentration: 11.0 mg/L for 72 hr; Effect: growth rate /technical grade MDA/ /Conditions of bioassay not specified in source examined/ European Chemicals Bureau; European Union Risk Assessment Report, 4,4-Methylenedianiline (101-77-9) p. 22 (2001). Available from, as of February 26, 2009: http://esis.jrc.ec.europa.eu/
from HSDB LC50; Species: Brachydanio rerio (Zebra danio); Conditions: static, nominal concentrations); Concentration: 42.0 mg/L for 96 hr /95.5-98% purity/ European Chemicals Bureau; European Union Risk Assessment Report, 4,4-Methylenedianiline (101-77-9) p. 19 (2001). Available from, as of February 26, 2009: http://esis.jrc.ec.europa.eu/
from HSDB LC50; Species: Brachydanio rerio (Zebra danio); Conditions: static, nominal concentrations); Concentration: 65.0 mg/L for 96 hr /99.7% purity/ European Chemicals Bureau; European Union Risk Assessment Report, 4,4-Methylenedianiline (101-77-9) p. 19 (2001). Available from, as of February 26, 2009: http://esis.jrc.ec.europa.eu/
from HSDB LC50; Species: Leuciscus idus (Ide); Conditions: static, nominal concentration); Concentration: 53.0 mg/L for 96 hr /96% purity/ European Chemicals Bureau; European Union Risk Assessment Report, 4,4-Methylenedianiline (101-77-9) p. 19 (2001). Available from, as of February 26, 2009: http://esis.jrc.ec.europa.eu/
from HSDB LC50; Species: Oryzias latipes (Japanese medaka); Conditions: static/semi-static; Concentration: 32.0 mg/L for 48 hr European Chemicals Bureau; European Union Risk Assessment Report, 4,4-Methylenedianiline (101-77-9) p. 19 (2001). Available from, as of February 26, 2009: http://esis.jrc.ec.europa.eu/
from HSDB LC50; Species: Oncorhynchus mykiss (Rainbow trout); Conditions: static, nominal concentration); Concentration: 39.0 mg/L for 96 hr /95.5-98% purity/ European Chemicals Bureau; European Union Risk Assessment Report, 4,4-Methylenedianiline (101-77-9) p. 19 (2001). Available from, as of February 26, 2009: http://esis.jrc.ec.europa.eu/
from HSDB
12.1.21 TSCA Test Submissions The potential for pure di-(4-aminophenyl)methane to induce urinary bladder cancer was evaluated in five six-month old female pure-bred beagle dogs each ingesting the test material in gelatin capsules at doses ranging from 4.95 to 6.26 g/kg/day, three days a week for seven years. Clinical chemistry evaluations (blood glucose, BUN, creatinine, total proteins, albumin and alkaline phosphatase activity) were performed on venous blood to detect liver or other systemic injury; all tests remained negative except for a marked elevation of blood alkaline phosphatase activity. Post mortum examination revealed severe liver injury which progressed to portal cirrhosis in two of the five dogs. None of the treatments induced neoplastic changes in the urinary bladder. University of Miami, The Chronic Toxicity of Di-(4-Aminophenyl)-Methane in Dogs, Final Report, (1971), EPA Document No 878210829, Fiche No OTS0206229
from HSDB 4,4'-Methylenedianiline was examined for mutagenic activity in Salmonella tester strains TA98 and TA100 in the presence and absence of metabolic activation provided by Aroclor induced rat liver S9 fraction. The test article was administered at concentrations ranging from 0.1 to 500 ug/plate by the plate incorporation technique. A mutagenic effect was observed in strain TA100, and a less pronounced effect in TA98, in the presence of metabolic activation beginning at 25 ug/plate. In the absence of activation, no mutagenic effect was observed in either strain. Cytotoxicity data was not reported. Upjohn Co.; Comparison of Results Obtained by Litton Bionetics and Dept. 7252 on the Mutagenicity of MDA (4,4'-methylenedianiline), (1976), EPA Document No. 878210679, Fiche No. OTS0206259
from HSDB 4,4'-Methylenedianiline was evaluated for mutagenic activity in Salmonella typhimurium tester strains TA1535, TA1537, TA1538 and Saccharomyces cerevisiae strain D4 in the absence and presence of metabolic activation provided by Sprague-Dawley rat, ICR mouse, or Rhesus monkey liver S9 fraction. Induction of enzyme activities prior to S9 fraction preparation was not
reported. Exposure to test article by the plate incorporation technique at a concentration of 1 mg/plate was not mutagenic in any strain with or without activation. Cytotoxicity data was not reported. Litton Bionetics; Mutagenic Evaluation of 4,4'- Methylenedianiline Using Microbial Plate Test Systems (1975), EPA Document No. 878211084, Fiche No. OTS0206259
from HSDB Mutagenicity of 4,4'-methylenedianiline was determined in the Salmonella typhimurium tester strains TA98, TA100, TA1535, TA1537 and TA1538 using the plate incorporation technique in the presence and absence of Aroclor-induced rat liver S9 metabolic activation. No mutagenic effect was observed in any strain when the test article was administered at concentrations of 0.1, 0.5, 1, 5, or 10 ug/plate, either with or without activation. The cytotoxicity of the test article at these concentrations was not reported. Microbiological Associates; MDA: Activity of Compound E in the Salmonella/Microsomal Assay for Bacterial Mutagenicity (1977), EPA Document No. 878211465, Fiche No. OTS0206019
from HSDB 4,4'-Methylenedianiline was evaluated for its ability to induce a mutagenic response in Salmonella typhimurium strains TA1535, TA1537, TA1538, TA98 and TA100, or gene conversion in Saccharomyces cerevisiae strain D4, when administered in the presence or absence of metabolic activation provided by Aroclor-induced rat liver S9. In the presence of activation, a weak mutagenic effect was observed in strains TA1538 and TA98 at applied test article concentrations ranging from 5 to 500 ug/plate, while in the absence of activation no mutagenic effect in any strain was observed. Negative results were observed under all conditions in S. cerevisiae. The investigators reported that test concentrations were chosen so that some toxicity was produced at the high dose. Litton Bionetics, Inc.; Mutagenicity Evaluation of BIO-75-136-CP-11707, Final Report (1976), EPA Document No. 878213608, Fiche No. OTS0206353
from HSDB
12.1.22 Populations at Special Risk ... The enzyme N-acetyltransferase exhibits polymorphism, slow acetylators will be prone to more toxic insult of 4,4'-methylenedianiline than fast acetylators... DHHS/ATSDR; Toxicological Profile for Methylenedianiline (PB/99/102568/AS) (August 1998). Available from, as of February 23, 2009: http://www.atsdr.cdc.gov/toxpro2.html#bookmark05
from HSDB
12.2 Ecological Information 12.2.1 ICSC Environmental Data The substance is harmful to aquatic organisms. It is strongly advised not to let the chemical enter into the environment. from ILO-ICSC
12.2.2 Environmental Fate/Exposure Summary 4,4'-Diaminodiphenylmethane's production and use as a chemical intermediate in the production of isocyanates and polyisocyanates for preparation of polyurethane foams and in spandex fibers, as curing agent for epoxy resins and urethane elastomers, in the production of polyamides, in the determination of tungsten and sulfates, in the preparation of azo dyes, and as a corrosion inhibitor may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 2.03X10-7 mm Hg at 25 deg C indicates 4,4'-diaminodiphenylmethane will exist in both the vapor and particulate phases in the atmosphere. Vapor-phase 4,4'-diaminodiphenylmethane will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 12.8 hours. Particulate-phase 4,4'-diaminodiphenylmethane will be removed from the atmosphere by wet or dry deposition. 4,4'-Diaminodiphenylmethane contains chromophores that absorb at wavelengths >290 nm and therefore may be susceptible to direct photolysis by sunlight. If released to soil, 4,4'diaminodiphenylmethane is expected to have slight to no mobility based upon Koc values ranging from of 3825 to 5681. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 5.3X10-11 atm-cu m/mole. 4,4'-Diaminodiphenylmethane is not expected to volatilize from dry soil surfaces based upon its vapor pressure. A 0% of theoretical BOD using activated sludge in the Japanese MITI test suggests that biodegradation will not be an important environmental fate process in soil. If released into water, 4,4'-diaminodiphenylmethane is expected to adsorb to suspended solids and sediment based upon the Koc values. 4,4'-Diaminodiphenylmethane, present at 100 mg/L, reached 0% of its theoretical BOD in 4 weeks using an activated sludge inoculum at 30 mg/L in the Japanese MITI test, suggesting that biodegradation will not be an important fate process in the aquatic environment. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. Measured BCF values of 3.0 to 14 suggest bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions. Occupational exposure to 4,4'-diaminodiphenylmethane may occur through inhalation of dust and dermal contact with this compound at workplaces where 4,4'diaminodiphenylmethane is produced or used. Use data indicate that the general population may be exposed to 4,4'-diaminodiphenylmethane via dermal contact with consumer products containing 4,4'-diaminodiphenylmethane. (SRC) from HSDB
12.2.3 Artificial Sources 4,4'-Diaminodiphenylmethane's production and use as a chemical intermediate in the production of isocyanates and polyisocyanates for preparation of polyurethane foams and in spandex fibers, as curing agent for epoxy resins and urethane elastomers, in the production of polyamides, in the determination of tungsten and sulfates, in the preparation of azo dyes, and as a corrosion
inhibitor(1) may result in its release to the environment through various waste streams(SRC). (1) O'Neil MJ, ed; The Merck Index. Whitehouse Station, NJ: Merck and Co., Inc. p. 506 (2006)
from HSDB
12.2.4 Environmental Fate TERRESTRIAL FATE: Based on a classification scheme(1), Koc values ranging from 3825 to 5681(2), indicate that 4,4'-diaminodiphenylmethane is expected to have slight to no mobility in soil(SRC). Volatilization of 4,4'-diaminodiphenylmethane from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 5.30X10-11 atm-cu m/mole(SRC), based upon its vapor pressure, 2.03X10-7 mm Hg(3), and water solubility, 1.00E+3(4). 4,4'-Diaminodiphenylmethane is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(3). A 0% of theoretical BOD using activated sludge in the Japanese MITI test(5) suggests that biodegradation will not be an important environmental fate process in soil(SRC). (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Cowen WF et al; Environ Sci Technol 32: 598-603 (1998) (3) Amini B, Lowenkron S; Kirk-Othmer Encyclopedia of Chemical Technology. (2005). NY, NY: John Wiley & Sons; Aniline and Its Derivatives. Online Posting Date: July 18, 2003. (4) Moore WM; Methylenedianiline In: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed. New York: Wiley & Sons 2: 338-48 (1978) (5) NITE; Chemical Risk Information Platform (CHRIP). Biodegradation and Bioconcentration. Tokyo, Japan: Natl Inst Tech Eval. Available at http://www.safe.nite.go.jp/english/db.html as of March 5, 2009.
from HSDB AQUATIC FATE: Based on a classification scheme(1), measured Koc values ranging from 3825 to 5681(2), indicate that 4,4'-diaminodiphenylmethane is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 5.30X10-11 atm-cu m/mole(SRC), derived from its vapor pressure, 2.03X10-7 mm Hg(4), and water solubility, 1.00E+3(5). According to a classification scheme(6), BCF values of 3.0 to 14(7) suggest the bioconcentration in aquatic organisms is low(SRC). 4,4'Diaminodiphenylmethane, present at 100 mg/L, reached 0% of its theoretical BOD in 4 weeks using an activated sludge inoculum at 30 mg/L in the Japanese MITI test(7), suggesting that biodegradation will not be an important fate process in the aquatic environment(SRC). (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Cowen WF et al; Environ Sci Technol 32: 598-603 (1998) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Amini B, Lowenkron S; Kirk-Othmer Encyclopedia of Chemical Technology. (2005). NY, NY: John Wiley & Sons; Aniline and Its Derivatives. Online Posting Date: July 18, 2003. (5) Moore WM; Methylenedianiline In: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed. New York: Wiley & Sons 2: 338-48 (1978) (6) Franke C et al; Chemosphere 29: 1501-14 (1994) (7) NITE; Chemical Risk Information Platform (CHRIP). Biodegradation and Bioconcentration. Tokyo, Japan: Natl Inst Tech Eval. Available at http://www.safe.nite.go.jp/english/db.html as of March 5, 2009.
from HSDB ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 4,4'-diaminodiphenylmethane, which has a vapor pressure of 2.03X10-7 mm Hg at 25 deg C(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase 4,4'-diaminodiphenylmethane is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 12.8 hours(SRC), calculated from its rate constant of 3.00X10-11 cu cm/molecule-sec at 25 deg C(3). Particulate-phase 4,4'-diaminodiphenylmethane may be removed from the air by wet or dry deposition(SRC). 4,4'-Diaminodiphenylmethane contains chromophores that absorb at wavelengths >290 nm(4) and therefore may be susceptible to direct photolysis by sunlight(SRC). (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Amini B, Lowenkron S; Kirk-Othmer Encyclopedia of Chemical Technology. (2005). NY, NY: John Wiley & Sons; Aniline and Its Derivatives. Online Posting Date: July 18, 2003. (3) Atkinson R; J Phys Chem Ref Data Monograph No. 1 (1989) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 8-12 (1990)
from HSDB
12.2.5 Biodegredation AEROBIC: 4,4'-Diaminodiphenylmethane, present at 100 mg/L, reached 0% of its theoretical BOD in 4 weeks using an activated sludge inoculum at 30 mg/L in the Japanese MITI test(1). Aerobic biodegradation of 4,4'-diaminodiphenylmethane in a silt loam soil (measured as the fraction of CO2 recovered) was 2, 10, 11.2, and 11.6% after 3, 14, 28, and 56 days, respectively(2). Apparent biodegradation after 365 days in the silt loam soil was reported as 40.1%(2). (1) NITE; Chemical Risk Information Platform (CHRIP). Biodegradation and Bioconcentration. Tokyo, Japan: Natl Inst Tech Eval. Available at http://www.safe.nite.go.jp/english/db.html as of March 5, 2009. (2) Cowen WF et al; Environ Sci Technol 32: 598-603 (1998)
from HSDB ANAEROBIC: After 71 days of incubation in anaerobic digester sludge mixed with silt loam soil, no biodegradation was observed for 4,4'-diaminodiphenylmethane(1). (1) Cowen WF et al; Environ Sci Technol 32: 598-603 (1998)
from HSDB
12.2.6 Abiotic Degredation The rate constant for the vapor-phase reaction of 4,4'-diaminodiphenylmethane with photochemically-produced hydroxyl radicals has been measured as 3.00X10-11 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 12.8 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(2). 4,4'-Diaminodiphenylmethane is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(3). 4,4'-Diaminodiphenylmethane contains chromophores that absorb at wavelengths >290 nm(3) and therefore may be susceptible to direct photolysis by sunlight(SRC). As a class, aromatic amines react relatively rapidly in sunlit natural water via reaction with photochemically produced hydroxyl radicals and peroxy radicals(4); typical half-lives for hydroxyl radical and peroxy radical reactions are on the order of 19 to 30 sunlight hours(4). Exposure of
crystalline 4,4'-diaminodiphenylmethane to air and light results in oxidation of the crystals(darkening in color) and the formation of polymeric amines(5,6). (1) Atkinson R; J Phys Chem Ref Data Monograph No. 1 (1989) (2) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5, 8-12 (1990) (4) Mill T, Mabey W; p.208-11 in Environmental Exposure from Chemicals Vol I, Neely WR, Blau GE eds Boca Raton, FL: CRC Press (1985) (5) Amini B, Lowenkron S; Kirk-Othmer Encyclopedia of Chemical Technology. (2005). NY, NY: John Wiley & Sons; Aniline and Its Derivatives. Online Posting Date: July 18, 2003. (6) IARC; IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Some Chemicals Used in Plastic and Elastomers. 39: 347-65 (1986)
from HSDB
12.2.7 Bioconcentration BCF values ranging from 3.0 to 14 were measured for 4,4'-diaminodiphenylmethane (200 ug/L) in carp (4.5% lipid content) after a 6 week period(1). According to a classification scheme(2), these BCF values suggest the bioconcentration in aquatic organisms is low(SRC). (1) NITE; Chemical Risk Information Platform (CHRIP). Biodegradation and Bioconcentration. Tokyo, Japan: Natl Inst Tech Eval. Available at http://www.safe.nite.go.jp/english/db.html as of March 5, 2009. (2) Franke C et al; Chemosphere 29: 1501-14 (1994)
from HSDB
12.2.8 Soil Adsorption/Mobility After an 8 hour sorption period, Koc values of 5681 and 3825 were measured for 4,4'-diaminodiphenylmethane in sandy loam under aerobic and anaerobic conditions, respectively(1). Koc values of 4015 and 3831 were measured in silt loam under aerobic and anaerobic conditions, respectively(1). According to a classification scheme(2), these measured Koc values suggest that 4,4'diaminodiphenylmethane is expected to have slight to no mobility in soil. The reaction of 4,4'-diaminodiphenylmethane with soil humics was studied by allowing the substance to remain in contact with soil for 7 days and then measuring desorption in 1 day. The results suggested that 4,4'-diaminodiphenylmethane sorbed onto soil may be in a relatively facile equilibrium with the surrounding solution as shown by the similarity of distribution ratios (sorbed compound (in ug/g of soil)/concentrated in solution (in ug/mL)) for both sorption and desorption with Rdesorb/Rsorb ranging from 1.1 to 1.4(1). In this study the average ratio of aerobic/anaerobic soil sorption coefficients for 4,4'-diaminodiphenylmethane was 1.27, suggesting little difference between the behavior of 4,4'diaminodiphenylmethane with soil under oxidizing and reducing conditions(1). Aromatic amines have been observed to undergo rapid and reversible covalent bonding with humic materials in aqueous solution; the initial bonding reaction is followed by a slower and much less reversible reaction believed to represent the addition of the amine to quinoidal structures followed by oxidation of the product to give an amino-substituted quinone; these processes represent pathways by which aromatic amines may be converted to latent forms in the biosphere(3). (1) Cowen WF et al; Environ Sci Technol 32: 598-603 (1998) (2) Swann RL et al; Res Rev 85: 17-28 (1983) (3) Parris GE; Environ Sci Technol 14: 1099-106 (1980)
from HSDB
12.2.9 Volatilization from Water/Soil The Henry's Law constant for 4,4'-diaminodiphenylmethane is estimated as 5.3X10-11 atm-cu m/mole(SRC) derived from its vapor pressure, 2.03X10-7 mm Hg(1), and water solubility, 1.00X10+3 mg/L(2). This Henry's Law constant indicates that 4,4'-diaminodiphenylmethane is expected to be essentially nonvolatile from water surfaces(3). 4,4'-Diaminodiphenylmethane's estimated Henry's Law constant indicates that volatilization from moist soil surfaces is not expected to occur(SRC). 4,4'-Diaminodiphenylmethane is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(1). (1) Amini B, Lowenkron S; Kirk-Othmer Encyclopedia of Chemical Technology. (2005). NY, NY: John Wiley & Sons; Aniline and Its Derivatives. Online Posting Date: July 18, 2003. (2) Moore WM; Methylenedianiline In: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed. New York: Wiley & Sons 2: 338-48 (1978) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990)
from HSDB
12.2.10 Probable Routes of Human Exposure NIOSH (NOES Survey 1981-1983) has statistically estimated that 15,170 workers (3,407 of these were female) were potentially exposed to 4,4'-diaminodiphenylmethane in the US(1). Occupational exposure to 4,4'-diaminodiphenylmethane may occur through inhalation of dust and dermal contact with this compound at workplaces where 4,4'-diaminodiphenylmethane is produced or used. Use data indicate that the general population may be exposed to 4,4'-diaminodiphenylmethane via dermal contact with consumer products containing 4,4'diaminodiphenylmethane(SRC). (1) NIOSH; NOES. National Occupational Exposure Survey conducted from 1981-1983. Estimated numbers of employees potentially exposed to specific agents by 2-digit standard industrial classification (SIC). Available from, as of March 5, 2009. http://www.cdc.gov/noes/
from HSDB TWA exposures to 4,4'-diaminodiphenylmethane at a Dow production facility ranged from 0.03 to 0.4 ppm; air concn ranged from 0.03 to 3.8 ppm, with the highest levels occurring during grinding and packaging operations(1). 4,4'-Diaminodiphenylmethane has been detected in the air of working areas during its production at levels of 0.2 to 31 mg/cu m, its use in the manufacture of insulating materials at levels of 0.8 mg/cu m, its use in a polyurethane encapsulation operation at levels of 10 ug/cu m, and in core-making operations (using polymer binders) at iron and steel foundries at levels up to 1.6 mg/cu m(2). A survey of a 4,4'-diaminodiphenylmethane production facility found personal and work area air samples containing 4,4'-diaminodiphenylmethane levels of 5 to 74 and 13 to 651 ug/cu m, respectively(2); dermal pads from the hands of chemical operators contained 4.2 to 54 ug/sq cm(2). A survey of reinforced plastics production (which use 4,4'diaminodiphenylmethane) found 4,4'-diaminodiphenylmethane personal and work area air samples containing 4,4'-diaminodiphenylmethane levels of 1 to 690 and <0.3 to 99 ug/cu m, respectively(2). (1) NCI; Monograph on Human Exposure to Chemicals in the Workplace: 4,4'-Methylenedianiline. Bethesda, MD: National Cancer Institute (1985) (2) IARC; IARC Monographs on the Evaluation of the
Carcinogenic Risk of Chemicals to Humans. Some Chemicals Used in Plastic and Elastomers. 39: 347-65 (1986)
from HSDB
12.2.11 Body Burdens Analysis of urine samples from 27 workers involved in the production of MDA found that 14.9% of all collected samples had levels above 200 ppb in 1970, while only 0.09% of collected samples had levels above 20 ppb in 1980(1). The urine samples of seven male workers (ages 24-44 years old) at a work site where 4,4'-diaminodiphenylmethane is used as a curing agent showed an elimitation rate of 0 to 90 umol/hr(2). The cumulated excretion amount ranged from 0.04 to 1.2 umol per day on workdays and 0.005 to 0.51 umol daily of weekends(2). The 4,4'diaminodiphenylmethane concentration in the workers' blood ranged from 10 to 60 nmol/L(2). Urine samples collected at the end of a workshift from workers exposed to 4,4'diaminodiphenylmethane contained average concentrations of 236 ug/g creatinine (collected from 91 workers in August 1988), 98 ug/g creatinine (collected from 87 workers in October 1988), 50 ug/g creatinine (collected from 20 workers in June 1989), 202 ug/g creatinine (collected from 107 workers in May 1990), and 43 ug/g creatinine (collected from 43 workers in June 1990)(3). (1) IARC; IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Some Chemicals Used in Plastic and Elastomers. 39: 347-65 (1986) (2) Dalene M et al; Int Arch Occup Environ Health 67: 67-72 (1995) (3) Kusters E; Br J Ind Med 49: 72 (1992)
from HSDB
13 Literature 13.1 Depositor Provided PubMed Citations LOADING... PLEASE WAIT...
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13.3 Metabolite References Download 1 to 3 of 3 PMID
Reference
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Pludro G, Karlowski K, Mankowska M, Woggon H, Uhde WJ: [Toxicological and chemical studies of some epoxy resins and hardeners. I. Study of acute and subacute toxicity of phthalic acid anhydride, 4,4'diaminodiphenylmethane and epoxy resin Epilox EG-34]. Acta Pol Pharm. 1969;26(4):353-8.
1150762 Yasuda SK: Determination of 3,3'-dichloro-4,4'-diaminodiphenylmethane in air. J Chromatogr. 1975 Feb 12;104(2):283-90. 6549168
Manis MO, Braselton WE Jr: Structure elucidation and in vitro reactivity of the major metabolite of 4,4'-methylenebis(2-chloroaniline) (MBOCA) in canine urine. Fundam Appl Toxicol. 1984 Dec;4(6):1000-8. from Human Metabolome Database (HMDB)
13.4 Springer Nature References LOADING... PLEASE WAIT...
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17 Information Sources 1. CAMEO Chemicals /source/CAMEO Chemicals 4,4'-DIAMINODIPHENYLMETHANE https://cameochemicals.noaa.gov/chemical/3080 https://cameochemicals.noaa.gov/chemical/3080 CAMEO Chemical Reactivity Classification https://cameochemicals.noaa.gov/browse/react https://cameochemicals.noaa.gov/browse/react
2. ChemIDplus /source/ChemIDplus 4,4'-Methylenedianiline https://chem.nlm.nih.gov/chemidplus/sid/0000101779 https://chem.nlm.nih.gov/chemidplus/sid/0000101779 ChemIDplus Chemical Information Classification https://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp https://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp
3. DTP/NCI /source/DTP/NCI 4,4'-Methylenedianiline https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=4709 https://dtp.cancer.gov/dtpstandard/servlet/dwindex? searchtype=NSC&outputformat=html&searchlist=4709
4. EPA Chemicals under the TSCA /source/EPA Chemicals under the TSCA Benzenamine, 4,4'-methylenebishttp://www.epa.gov/chemical-data-reporting http://www.epa.gov/chemical-data-reporting
5. EPA DSStox /source/EPA DSStox 4,4'-Methylenedianiline https://comptox.epa.gov/dashboard/dsstoxdb/results?search=DTXSID6022422 https://comptox.epa.gov/dashboard/dsstoxdb/results?search=DTXSID6022422
6. European Chemicals Agency - ECHA /source/European Chemicals Agency - ECHA 4,4'-methylenedianiline https://www.echa.europa.eu https://www.echa.europa.eu 4,4'-methylenedianiline https://www.echa.europa.eu/web/guest/information-on-chemicals/cl-inventory-database/-/discli/details/20502 https://www.echa.europa.eu/web/guest/information-on-chemicals/cl-inventory-database//discli/details/20502
7. Human Metabolome Database (HMDB) /source/Human Metabolome Database (HMDB) 4,4'-Methylenedianiline http://www.hmdb.ca/metabolites/HMDB0041808 http://www.hmdb.ca/metabolites/HMDB0041808
8. ILO-ICSC /source/ILO-ICSC 4,4'-METHYLENEDIANILINE http://www.ilo.org/dyn/icsc/showcard.display?p_version=2&p_card_id=1111 http://www.ilo.org/dyn/icsc/showcard.display?p_version=2&p_card_id=1111
9. The National Institute for Occupational Safety and Health - NIOSH /source/The National Institute for Occupational Safety and Health - NIOSH Aniline, 4,4'-methylenedihttps://www.cdc.gov/niosh-rtecs/BY52C768.html https://www.cdc.gov/niosh-rtecs/BY52C768.html 4,4'-Methylenedianiline https://www.cdc.gov/niosh/npg/npgd0415.html https://www.cdc.gov/niosh/npg/npgd0415.html
10. DOT Emergency Response Guidebook /source/DOT Emergency Response Guidebook 4,4'-diaminodiphenylmethane http://phmsa.dot.gov/hazmat/outreach-training/erg http://phmsa.dot.gov/hazmat/outreach-training/erg
11. NJDOH RTK Hazardous Substance List /source/NJDOH RTK Hazardous Substance List 4,4'-methylene dianiline http://nj.gov/health/eoh/rtkweb/documents/fs/1256.pdf http://nj.gov/health/eoh/rtkweb/documents/fs/1256.pdf
12. CDC-ATSDR Toxic Substances Portal /source/CDC-ATSDR Toxic Substances Portal 4,4'-Methylenedianiline https://www.atsdr.cdc.gov/substances/toxsubstance.asp?toxid=210 https://www.atsdr.cdc.gov/substances/toxsubstance.asp?toxid=210
13. EPA Air Toxics /source/EPA Air Toxics 4,4-Methylenedianiline https://www.epa.gov/sites/production/files/2016-09/documents/meth-dia.pdf https://www.epa.gov/sites/production/files/2016-09/documents/meth-dia.pdf
14. HSDB /source/HSDB 4,4'-DIAMINODIPHENYLMETHANE
https://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+101-77-9 https://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+101-77-9
15. EU REGULATION (EC) No 1272/2008 /source/EU REGULATION (EC) No 1272/2008 4,4'-diaminodiphenylmethane;4,4'-methylenedianiline http://ec.europa.eu/growth/sectors/chemicals/classification-labelling/index_en.htm http://ec.europa.eu/growth/sectors/chemicals/classification-labelling/index_en.htm
16. NITE-CMC /source/NITE-CMC 4,4'-Methylenedianiline http://www.safe.nite.go.jp/english/ghs/14-mhlw-2204e.html http://www.safe.nite.go.jp/english/ghs/14-mhlw-2204e.html
17. Safe Work Australia - HCIS /source/Safe Work Australia - HCIS 4,4'-diaminodiphenylmethane http://hcis.safeworkaustralia.gov.au/HazardousChemical/Details?chemicalID=1197 http://hcis.safeworkaustralia.gov.au/HazardousChemical/Details?chemicalID=1197
18. FDA Center for Food Safety and Applied Nutrition (CFSAN) /source/FDA Center for Food Safety and Applied Nutrition (CFSAN) 4,4'-METHYLENEDIANILINE https://www.accessdata.fda.gov/scripts/fdcc/index.cfm?set=IndirectAdditives&id=METHYLENEDIANILINE https://www.accessdata.fda.gov/scripts/fdcc/index.cfm? set=IndirectAdditives&id=METHYLENEDIANILINE
19. FDA/SPL Indexing Data /source/FDA/SPL Indexing Data GG5LL7OBZC https://www.fda.gov/ForIndustry/DataStandards/SubstanceRegistrationSystem-UniqueIngredientIdentifierUNII/ https://www.fda.gov/ForIndustry/DataStandards/SubstanceRegistrationSystemUniqueIngredientIdentifierUNII/
20. SpectraBase /source/SpectraBase https://spectrabase.com/compound/Ft7NZzmTKXZ#3ISj9TxOqNC https://spectrabase.com/compound/Ft7NZzmTKXZ#3ISj9TxOqNC https://spectrabase.com/compound/Ft7NZzmTKXZ#4DUp6OP5yn2 https://spectrabase.com/compound/Ft7NZzmTKXZ#4DUp6OP5yn2 https://spectrabase.com/compound/Ft7NZzmTKXZ#BRX36Fox0Mm https://spectrabase.com/compound/Ft7NZzmTKXZ#BRX36Fox0Mm https://spectrabase.com/compound/Ft7NZzmTKXZ#9PFsELp4fO5 https://spectrabase.com/compound/Ft7NZzmTKXZ#9PFsELp4fO5 https://spectrabase.com/compound/Ft7NZzmTKXZ#7UGmCwgh2JI https://spectrabase.com/compound/Ft7NZzmTKXZ#7UGmCwgh2JI https://spectrabase.com/compound/Ft7NZzmTKXZ#37atlXr5EYs https://spectrabase.com/compound/Ft7NZzmTKXZ#37atlXr5EYs https://spectrabase.com/compound/Ft7NZzmTKXZ#1kA0OARXw3p https://spectrabase.com/compound/Ft7NZzmTKXZ#1kA0OARXw3p https://spectrabase.com/compound/Ft7NZzmTKXZ#IeyzvpnNcou https://spectrabase.com/compound/Ft7NZzmTKXZ#IeyzvpnNcou https://spectrabase.com/compound/Ft7NZzmTKXZ#A3UEGQJHqqS https://spectrabase.com/compound/Ft7NZzmTKXZ#A3UEGQJHqqS
21. NIOSH Manual of Analytical Methods /source/NIOSH Manual of Analytical Methods 101-77-9 http://www.cdc.gov/niosh/docs/2003-154/pdfs/5029.pdf http://www.cdc.gov/niosh/docs/2003-154/pdfs/5029.pdf
22. NIST /source/NIST Benzenamine, 4,4'-methylenebishttp://www.nist.gov/srd/nist1a.cfm http://www.nist.gov/srd/nist1a.cfm
23. OSHA Chemical Sampling Information /source/OSHA Chemical Sampling Information 4,4'-Methylenedianiline https://www.osha.gov/dts/chemicalsampling/data/CH_253500.html https://www.osha.gov/dts/chemicalsampling/data/CH_253500.html
24. Springer Nature /source/Springer Nature Literature references related to scientific contents from Springer Nature journals and books. Read more ... https://link.springer.com/
25. The Cambridge Structural Database /source/The Cambridge Structural Database The Cambridge Structural Database provides access to 3D structures of molecules determined experimentally using diffraction techniques. http://www.ccdc.cam.ac.uk/pages/Home.aspx http://www.ccdc.cam.ac.uk/pages/Home.aspx
26. Wikipedia /source/Wikipedia 4,4 ¢-methylenedianiline https://en.wikipedia.org/wiki/4,4%27-Methylenedianiline https://en.wikipedia.org/wiki/4,4%27-Methylenedianiline
27. PubChem Data deposited in or computed by PubChem https://pubchem.ncbi.nlm.nih.gov https://pubchem.ncbi.nlm.nih.gov
28. MeSH /source/MeSH 4,4'-diaminodiphenylmethane https://www.ncbi.nlm.nih.gov/mesh/67009505 https://www.ncbi.nlm.nih.gov/mesh/67009505 MeSH Tree http://www.nlm.nih.gov/mesh/meshhome.html http://www.nlm.nih.gov/mesh/meshhome.html Carcinogens https://www.ncbi.nlm.nih.gov/mesh/68002273 https://www.ncbi.nlm.nih.gov/mesh/68002273
29. ChEBI /source/ChEBI ChEBI Ontology http://www.ebi.ac.uk/chebi/userManualForward.do#ChEBI%20Ontology http://www.ebi.ac.uk/chebi/userManualForward.do#ChEBI%20Ontology
30. KEGG /source/KEGG Carcinogens http://www.genome.jp/kegg-bin/get_htext?br08008.keg http://www.genome.jp/kegg-bin/get_htext?br08008.keg
31. WIPO /source/WIPO International Patent Classification http://www.wipo.int/classifications/ipc/ http://www.wipo.int/classifications/ipc/
32. NCBI LinkOut is a service that allows one to link directly from NCBI databases to a wide range of information and services beyond NCBI systems. https://www.ncbi.nlm.nih.gov/projects/linkout https://www.ncbi.nlm.nih.gov/projects/linkout