Long-term toxicity and carcinogenicity studies with 2,4/2,6-toluene-diisocyanate (80/20) in rats and mice

Loeser, Edward A.

doi:10.1016/0378-4274(83)90172-8

Cited by 54 publications

(29 citation statements)

References 7 publications

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“…A testament to the influence of pH on the conversion of TDI to TDA is the laboratory practice of using acid hydrolyses to convert TDI/TDA conjugates in biological fluids to free TDA (Skarping et al, 1994). The in vivo conversion of TDI to TDA and the subsequent induction of a carcinogenic response only under aphysiological (i.e., gavage) exposure conditions is consistent with the observations that (a) lifetime inhalation exposures of rodents to TDI vapor at a maximum tolerated concentration of 150 ppb did not elicit a carcinogenic response (Löser, 1983;Owen, 1984), (b) free TDA was not detected in rats following a 6-h inhalation exposure to TDI vapor at 2 ppm (Timchalk et al, 1994), a concentration 400-fold higher than the TDI TLV, (c) free TDA was not detected in the urine of TDI exposed workers before subjection to acid hydrolysis (Skarping et al, 1994), and (d) three epidemiological studies with updates, representing the combined long-term mortality experience of more than 17,000 PU foam production workers, failed to find an association between occupational exposure to diisocyanates and an increased risk of cancer (Hagmar et al, 1993a,b, updated by Mikoczy et al, 2004Schnorr et al, 1996;Pope, 1993, updated by Sorahan andNichols, 2002).…”

Section: Carcinogenicitysupporting

confidence: 72%

Risk assessment for consumer exposure to toluene diisocyanate (TDI) derived from polyurethane flexible foam

Arnold

Collins²,

Graham

et al. 2012

Regulatory Toxicology and Pharmacology

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Polyurethanes (PU) are polymers made from diisocyanates and polyols for a variety of consumer products. It has been suggested that PU foam may contain trace amounts of residual toluene diisocyanate (TDI) monomers and present a health risk. To address this concern, the exposure scenario and health risks posed by sleeping on a PU foam mattress were evaluated. Toxicity benchmarks for key non-cancer endpoints (i.e., irritation, sensitization, respiratory tract effects) were determined by dividing points of departure by uncertainty factors. The cancer benchmark was derived using the USEPA Benchmark Dose Software. Results of previous migration and emission data of TDI from PU foam were combined with conservative exposure factors to calculate upper-bound dermal and inhalation exposures to TDI as well as a lifetime average daily dose to TDI from dermal exposure. For each non-cancer endpoint, the toxicity benchmark was divided by the calculated exposure to determine the margin of safety (MOS), which ranged from 200 (respiratory tract) to 3×10(6) (irritation). Although available data indicate TDI is not carcinogenic, a theoretical excess cancer risk (1×10(-7)) was calculated. We conclude from this assessment that sleeping on a PU foam mattress does not pose TDI-related health risks to consumers.

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Section: Carcinogenicitysupporting

confidence: 72%

Risk assessment for consumer exposure to toluene diisocyanate (TDI) derived from polyurethane flexible foam

Arnold

Collins²,

Graham

et al. 2012

Regulatory Toxicology and Pharmacology

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“…There was some evidence of a decrease in polychromatic erythrocytes in the bone marrow, possibly indicating cytotoxicity. Loeser (33) reported that after inhalation exposure to TDI at 0.05 or 0.15 ppm (6 hours/day, 5 days/week) for four weeks to rats and mice of both sexes, there was no dose-or treatment-related percentage increase in micronucleated erythrocytes. Unscheduled DNA synthesis was assessed in hepatocyte cultures and lung explants harvested from rats after single four-hour inhalation exposure to 1.5 ppm TDI, and after four four-hour exposures to 0.9 ppm TDI.…”

Section: In Vivo Predictive Genotoxicity Testsmentioning

confidence: 97%

“…Loeser (33) reported on an investigation of inhalation exposure of rats and mice of both sexes to commercial grade TDI. The exposure was to TDI vapor at 0, 0.05, or 0.15 ppm, six hours/day, ve days/week for 108 to 110 weeks (rats), or 104 weeks (mice).…”

Section: Carcinogenicity: Inhalation Studiesmentioning

confidence: 99%

Toxicology of Toluene Diisocyanate

Collins¹

2002

Applied Occupational and Environmental Hygiene

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In studies on animals, toluene diisocyanate (TDI) was a contact and respiratory sensitizer, was not toxic by the oral or dermal routes, but was irritating, and toxic by inhalation. The respiratory tract was the target in acute, subchronic, and chronic exposure studies. Typically, at concentrations of above 0.1 ppm (parts per million), clinical signs of nasal irritation were evident, and histopathological investigations revealed rhinitis and epithelial hyperplasia of nasal passages. With increasing concentration, effects were more severe; affected the larynx, trachea, and lung; and, eventually, affected body weight and survival. The carcinogenicity of TDI to rats and mice was investigated. By inhalation, there was no treatment-related increase in tumor incidence in either species at the highest concentration tested (0.15 ppm). Effects of TDI were seen as rhinitis in nasal turbinates of both species, and as reduced body weight gain in mice. Through oral administration of TDI dissolved in corn oil to rats and mice (up to 120 mg/kg/day), increased incidence of a number of tumor types was seen. This route is of questionable relevance to occupational exposure. The dosing solutions were known to have degraded, and TDI would hydrolyze to diaminotoluene in the acidic stomach environment. Several in vitro tests for genotoxicity gave positive results, which can be ascribed to degradation of TDI by solvents. In properly conducted assays, in vivo TDI was negative for genotoxicity. In a two-generation reproduction study in rats, there were no effects on reproductive indices at the highest exposure concentration of 0.3 ppm TDI, which elicited toxicity in both generations. In a developmental toxicity study in rats, there was evidence of minimal fetotoxicity in the presence of maternal toxicity at 0.5 ppm, with no effects at 0.1 ppm. No treatment-related embryotoxicity or teratogenicity was observed.

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“…Ab 4,5 ml/m 3 starben Ratten mit Zeichen starker Schädigungen des Lungen-und Trachealgewebes (Henschler et al 1962;Zapp 1957). Für Meerschweinchen und Kaninchen waren 9 ml/m 3 noch nicht letal (Zapp 1957 , 1984Löser 1983; vgl. Abschnitt 5.7.2).…”

Section: Dermale Aufnahmeunclassified

“…In Tabelle 7 ist die Zahl nur für die Tumoren angegeben, die in den TDI-behandelten Gruppen um mindestens 2 höher lagen als in den mitgeführten Kontrollen. Nach Ansicht der Autoren war das Tumorspektrum in allen Gruppen unauffällig, so daß für TDI keine kanzerogene Wirkung abgeleitet wurde (International Isocyanate Institute 1980, 1984Löser 1983 (Maita et al 1988;Sher et al 1982 (Dieter et al 1990;NTP 1986 …”

Section: Langzeitstudienunclassified

Toluylendiisocyanate [MAK Value Documentation in German language, 1999]

2012

The MAK‐Collection for Occupational Health and Safety

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Veröffentlicht in der Reihe Gesundheitsschädliche Arbeitsstoffe , 28. Lieferung, Ausgabe 1999 Der Artikel enthält folgende Kapitel: Allgemeiner Wirkungscharakter Wirkungsmechanismus Toxikokinetik und Metabolismus Erfahrungen beim Menschen Einmalige Exposition Wiederholte Exposition Wirkung auf Haut und Schleimhäute Allergene Wirkung Reproduktionstoxizität Genotoxizität Kanzerogenität Tierexperimentelle Befunde und In‐vitro‐Untersuchungen Akute Toxizität Subakute, subchronische und chronische Toxizität Wirkung auf Haut und Schleimhäute Allergene Wirkung Reproduktionstoxizität Genotoxizität Kanzerogenität Bewertung

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Long-term toxicity and carcinogenicity studies with 2,4/2,6-toluene-diisocyanate (80/20) in rats and mice

Cited by 54 publications

References 7 publications

Risk assessment for consumer exposure to toluene diisocyanate (TDI) derived from polyurethane flexible foam

Risk assessment for consumer exposure to toluene diisocyanate (TDI) derived from polyurethane flexible foam

Toxicology of Toluene Diisocyanate

Toluylendiisocyanate [MAK Value Documentation in German language, 1999]

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