Di-(4-aminophenyl)-methane (MDA): 4–7 year dog feeding study

Deichmann, William B.; MacDonald, W.E.; Coplan, Milton M.; Woods, F.; Blum, E

doi:10.1016/s0300-483x(78)91089-2

Cited by 36 publications

(3 citation statements)

References 2 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The compound has a low mammalian toxicity with an oral LD 50 in mice, rats, guinea pigs, and rabbits which range between 200 and 800 mg/kg (1). It has been reported to be hepatotoxic in rats (2), dogs (3), and man (4). It was mutagenic in the Ames test (5) in the presence of an S9 metabolizing system and carcinogenic in rats and mice (2).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Quantification of DNA Adducts of 4,4‘-Methylenedianiline

Schutze

Sagelsdorff²,

Sepai³

et al. 1996

Chem. Res. Toxicol.

View full text Add to dashboard Cite

4,4'-Methylenedianiline (MDA) is used as a hardener in the manufacture of plastics and polyurethanes. MDA has been classified as a carcinogen in animals and is a suspected human carcinogen. Assuming that MDA would yield similar DNA adducts to other arylamines, we synthesized the following C-8 guanine adducts: N'-acetyl-N-(deoxyguanosin-8-yl)-MDA, N-(deoxyguanosin-8-yl)-MDA, N-(deoxyguanosin-8-yl)-4MA, and their corresponding 3'-monophosphate derivatives. We developed methods to identify these adducts of MDA in liver DNA using 32P-postlabeling, HPLC, and GC-MS techniques. 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.

show abstract

Section: Introductionmentioning

confidence: 99%

Synthesis and Quantification of DNA Adducts of 4,4‘-Methylenedianiline

Schutze

Sagelsdorff²,

Sepai³

et al. 1996

Chem. Res. Toxicol.

View full text Add to dashboard Cite

show abstract

“…4 Electron impact mass spectra obtained after fractionation of urine from a worker exposed to (a) DDM and (b) pure N-acetyl DDM. 106 624 monitoring exercises were carried out, factory D was found to have the greatest evidence of absorption of DDM among the workforce whereas no DDM was found in the urine of the workers in factory B.The results of the time course experiment in which DDM is released by two different hydrolysis procedures are shown in table 2.…”

mentioning

confidence: 99%

Assessment of occupational exposure to 4,4'-diaminodiphenylmethane (methylene dianiline) by gas chromatography-mass spectrometry analysis of urine.

Cocker¹,

Gristwood²,

Wilson³

1986

Occupational and Environmental Medicine

View full text Add to dashboard Cite

A new specific and sensitive method has been used to monitor workers from five different factories where 4,4'-diaminodiphenylmethane (methylene dianiline) (DDM) was being used. The isolation and identification of an N-acetyl conjugate of DDM, a major metabolite of DDM found in human urine, is reported for the first time. The use of this biological monitoring method will allow the assessment of the absorption of DDM and help in monitoring improvements in work practices, particularly where exposure may occur through pathways other than inhalation.4,4' Diaminodiphenylmethane (DDM) is a commercially important aromatic amine used in the production of isocyanates, polyisocyanates, polyurethane foams, and elastomers and as an epoxy resin hardener.' It is commonly referred to as methylene dianiline (MDA) (CAS 101-77-9). Several workers have studied the toxicity of DDM. It has been reported to be hepatoxic in rats,2 3 dogs,4 and man.5 It is mutagenic in the Ames test in the presence, but not in the absence, of an S9 metabolising system9 and has been reported to be carcinogenic in rats and mice.'0 " I As a result of these findings and the close chemical similarity of DDM to other aromatic amines, which are proved or suspect human carcinogens, DDM is under scrutiny by regulatory bodies in the United States.Occupational exposure to DDM may be assessed by measuring DDM concentrations in the work environment and by biological monitoring. DDM, like 3,3'-dichloro 4,4'-diaminodiphenylmethane (commonly known as 4,4' methylene bis 2-chloroaniline or MBOCA) and other aromatic amines, has the potential for considerable skin absorption. Analysis of urine samples from workers exposed to MBOCA is helpful in assessing absorption and in monitoring improvements in occupational hygiene.'2 Analytical methods have been reported for the analysis of DDM in workplace air using high performance liquid chromatography (HPLC) with ultraviolet detection'3 and in blood using gas chromatography (GC) with elecAccepted 3 March 1986. tron capture detection.'4 The work reported here describes the use of a new sensitive and specific gas chromatographic-mass spectrometric (GCMS) method for measuring DDM in urine. This approach was adopted after we had used HPLC and GC methods and had noted that occasionally interfering peaks were present in urine. We also describe for the first time the isolation and identification of N-acetyl DDM, a major metabolite of DDM found in human urine. These findings are used to devise a biological monitoring method for monitoring workers exposed to DDM. Materials and methods URINE SAMPLESUrine samples were collected from 111 workers at five factories using DDM. Factories A and B were packaging DDM as a component of a hardener in a two part epoxy resin formulation, factories C and D were using DDM and other compounds to impregnate carbon fibre mats, and factory E used DDM as a component in a screen printing process for seals and gaskets. Urine samples were collected in polycarbonate bottles towards the end of a working sh...

show abstract

“…Excepting for the author's report, there has been an absence of reports describing the formation of MDA and other toxic and mutagenic compounds in sterilized thermoplastic and thermosetting PUs when subjected to gamma-ray irradiation or autoclave sterilization so far [9,14]. The carcinogenicity and toxicity of MDA has previously been reported [2][3][4][19][20][21][22][23][24][25][26][27][28][29][30]. The MDA content was determined using a high performance liquid chromatography (HPLC) combined with an electrochemical detector (ECD) and ultraviolet (UV) detection simultaneously.…”

Section: Introductionmentioning

confidence: 99%

Formation and Elution of Toxic Compounds from γ-Ray Sterilized Medical Products: Toxic Compound Formation and Ames test of Eluted Components

Shintani¹

2012

Pharm Anal Acta

View full text Add to dashboard Cite

No formation of MDA was observed in chain-extended thermoplastic polyurethane (PU) when sterilized by autoclave or γ-ray irradiation. No formation of MDA was observed in nonchain-extended thermoplastic PU when sterilized by γ-ray irradiation. Less than 1 ppm of MDA was produced in nonchain-extended thermoplastic PU sterilized by autoclave sterilization. Autoclave sterilization did not produce MDA in thermosetting PU potting material. MDA formation in potting material was promoted by γ-ray irradiation and increased with increasing irradiation doses at a quadratic equation of regression. MDA formation at 100 kGy irradiation is a few ppm and less than one ppm at 25 kGy irradiation, therefore the potential risk to human recipients was not significant. The elution of compounds other than MDA from potting material was more problematic. Solvent extracts from potting material presented mutagenicity in the absence of metabolic activity (S9Mix). MDA presented mutagenicity in the presence of metabolic activity; therefore MDA was not the major mutagenic candidate. The chemical and biological characteristics of the specific mutagens required to identify in a further study. Negative promotion of MDA formation and a lesser presence of mutagen in autoclave sterilized potting material indicated that autoclave sterilization was preferable if the material is tolerable to heating.

show abstract

Di-(4-aminophenyl)-methane (MDA): 4–7 year dog feeding study

Cited by 36 publications

References 2 publications

Synthesis and Quantification of DNA Adducts of 4,4‘-Methylenedianiline

Synthesis and Quantification of DNA Adducts of 4,4‘-Methylenedianiline

Assessment of occupational exposure to 4,4'-diaminodiphenylmethane (methylene dianiline) by gas chromatography-mass spectrometry analysis of urine.

Formation and Elution of Toxic Compounds from γ-Ray Sterilized Medical Products: Toxic Compound Formation and Ames test of Eluted Components

Contact Info

Product

Resources

About