Mutagenicity of N-acetyl and N,N′-diacetyl derivatives of 3 aromatic amines used as epoxy-resin hardeners

Tanaka, Kenichi; Ino, T.; Sawahata, Tadashi; Marui, Shogo; Igaki, Hiroyuki; Yashima, H.

doi:10.1016/0165-7992(85)90097-1

Cited by 38 publications

(12 citation statements)

References 15 publications

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“…N-Acetyl-MDA is a major metabolite in urine samples of workers exposed to MDA (Robert et al, 1995;Schutze et al, 1995) or MDI Dalene et al, 1996). Both the N-acetyl and the N,NЈ-diacetyl-MDA metabolites have been identified in urine after administration of MDA (Tanaka et al, 1985) or MDI (Gledhill et al, 2005) to rats. Whereas N-acetyl-MDA represents more than half of all MDA metabolites in human urine in MDA-exposed workers, the N,NЈ-diacetyl-MDA metabolite represents Ͻ3%.…”

mentioning

confidence: 99%

4,4′-Methylenedianiline-Induced Hepatotoxicity Is Modified by N-Acetyltransferase 2 (NAT2) Acetylator Polymorphism in the Rat

Zhang

Lambert²,

Doll³

et al. 2005

J Pharmacol Exp Ther

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4,4Ј-Methylenedianiline (MDA) is widely used in the manufacturing of polyurethane foam, epoxy resins, and polymers. Exposure to MDA induces liver damage in humans and rats. 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. Recombinant expression of rat Nats in Escherichia coli showed that MDA was acetylated by both recombinant rat Nat1 and Nat2 and was catalyzed at substantially higher rates by rapid acetylator Nat2 compared with slow acetylator Nat2. Rapid acetylator F344 rat liver cytosols catalyzed the N-acetylation of MDA at significantly higher rates than those from slow acetylator Wistar-Kyoto (WKY) inbred rats. To test the effect of NAT2 genetic polymorphism on hepatotoxicity from acute MDA exposure, we 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 Ͻ 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.

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mentioning

confidence: 99%

4,4′-Methylenedianiline-Induced Hepatotoxicity Is Modified by N-Acetyltransferase 2 (NAT2) Acetylator Polymorphism in the Rat

Zhang

Lambert²,

Doll³

et al. 2005

J Pharmacol Exp Ther

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“…In TA1537 and TA100, mutagenicity was also found without metabolic activation [14]. The metabolite, N-acetyl-4,4'-oxydianiline, was mutagenic in the presence of S9 mix in the strains TA98 and TA100; N,N'-diacetyl-4,4'-oxydianiline was not mutagenic [2].…”

Section: Genotoxicitymentioning

confidence: 89%

“…The diacetyl metabolite was the main component. The peak of metabolite excretion was within the first 24 hours [2].…”

Section: Pharmacokineticsmentioning

confidence: 99%

4,4′‐Oxydianiline [MAK Value Documentation, 1993]

2012

The MAK‐Collection for Occupational Health and Safety

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Published in the series Occupational Toxicants , Vol. 6 (1993) The article contains sections titled: Toxic Effects and Modes of Action Pharmacokinetics Effects in Man Effects on Animals Acute toxicity Dermal toxicity Subchronic and chronic toxicity Sensitization tests Genotoxicity Carcinogenicity Manifesto (MAK value, classification)

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“…4 MDA, a curing agent for epoxy resins and urethane elastomers, is carcinogenic and mutagenic. [5][6][7][8] It can be eluted from PU, especially after the PU is sterilized by g radiation, 9 and thus may affect genotoxicity test results. Here we prepared three extracts-a culture medium extract and two organicsolvent extracts (methanol and acetone)-and determined how they influenced CA test results.…”

Section: Introductionmentioning

confidence: 99%

Organic‐solvent extraction of model biomaterials for use in the in vitro chromosome aberration test

Matsuoka

Haishima

Hasegawa

et al. 2007

J Biomedical Materials Res

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We prepared polyurethane (PU) containing 0.4% or 4% 4,4'-methylenedianiline (MDA) as model materials to investigate the effectiveness of sample preparation by organic-solvent extraction for the in vitro chromosome aberration (CA) test. MDA itself (0.4 mg/mL) was positive only in the presence of an exogenous metabolizing system (S9 mix). The culture medium extract of PU containing 4% MDA (PU/4% MDA) was negative with and without S9 mix. Methanol and acetone extracts, on the other hand, induced structural CAs without S9 mix, which we did not expect because MDA requires S9 mix for activity. On chemical analysis, however, we found that the ratio of MDA extracted by the organic solvents to that extracted by the culture medium of PU/4% MDA was about 15:1. Interestingly, oligomers consisting of poly(tetramethyleneglycol) derivatives (OTMG) were also extracted by the organic solvents. The data suggest that the induction of structural CAs in the absence of S9 mix may have been partly due to synergism of MDA and OTMG. CA tests of MDA and PTMG-1000 in combination confirmed that to be the case. Thus, organic-solvent extraction may be more effective than medium extraction in evaluating the biological safety of biomaterials. Detailed chemical analysis of extracts was performed.

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Mutagenicity of N-acetyl and N,N′-diacetyl derivatives of 3 aromatic amines used as epoxy-resin hardeners

Cited by 38 publications

References 15 publications

4,4′-Methylenedianiline-Induced Hepatotoxicity Is Modified by N-Acetyltransferase 2 (NAT2) Acetylator Polymorphism in the Rat

4,4′-Methylenedianiline-Induced Hepatotoxicity Is Modified by N-Acetyltransferase 2 (NAT2) Acetylator Polymorphism in the Rat

4,4′‐Oxydianiline [MAK Value Documentation, 1993]

Organic‐solvent extraction of model biomaterials for use in the in vitro chromosome aberration test

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