N-(4-aminophenyl)aniline

Endpoint summary

Additional information

In vitro studies

In vitro studies with everted rat intestine showed that 4-Aminodiphenylamine (4-ADPA) passes from the mucosal to the serosal side of gut in a concentration dependent manner, probably by passive diffusion (Raza 1982a).

In vitro studies demonstrated that 4-ADPA can be bound to proteins and collagen in rat skin (Khanna 1987, Tewari 1989). 4-ADPA binds to liver tissue proteins after incubation of liver slices (Srivastava 1982a) and to mucosal proteins of everted gut sacs (Raza 1982b). The 4-ADPA protein association is dependent from pH, the presence of metal ions and the absence of reducing agents. The authors suggested formation of a quinine structure which then binds to dicaboxylic acids of the proteins (Raza 1982b, Srivastava 1982a). In vitro studies on the binding of 4-ADPA to rat serum proteins showed that 4-ADPA has a higher binding affinity to serum globulin than to serum albumin. Electrophoretic studies indicated a stable binding involving electrostatic forces and hydrophobic interactions (Raza 1983).

In vivo studies

The absorption and elimination of 4-Aminodiphenylamine (4-ADPA) were evaluated in female CD® rats. Groups of four female rats received single doses of 14C labeled 4-ADPA by the oral (gavage), dermal or intravenous routes. In order to investigate whether the vehicle has an influence on the absorption of 4-ADPA from the gastro-intestinal tract, one group was given the test substance (200 mg/kg bw) in corn oil, and another group received the same dose in propylene glycol. In-life blood samples were taken from each animal 2 hours after dosing, and then in 24-hours intervals until sacrifice. Samples of urine and feces were collected from each animal at 24-hour intervals. The body burden of 14C at the end of the 7day observation period was determined by analyzing blood and carcasses. The use of propylene glycol caused a significant increase in the amount of 4-ADPA derived radioactivity excreted in the urine as compared to corn oil, which, according to the authors, may have been the result of an about 1.4 times greater absorption of 4-ADPA from the propylene glycol preparation as compared to the corn oil preparation. Peak blood concentrations of 4-ADPA derived radioactivity from the propylene glycol vehicle were almost double that of corn oil vehicle, and were not reached until 24 hours after dosing. The half-life of 4-ADPA in the blood was calculated as 11.6 days for 4-ADPA derived radioactivity from the corn oil preparation and 13.7 days for ADPA derived radioactivity from propylene glycol preparation. Plasma clearance after intravenous injection (2 mg/kg bw) consist of a short alpha-phase with a half-life of less than one day, followed by much longer beta phase of 12 days. The bioavailability of 4-ADPA in the 4-ADPA/corn oil animals was only about 54 % of those administered 4-ADPA in propylene glycol.

About 20 % of the applied dermal dose (2 mg/kg bw in ethanol) was absorbed through the skin. Approximately 80 % of the oral dose in corn oil, 88% of the oral dose in propylene glycol, 80% of the intravenous and 15 % of the dermal dose were eliminated in the urine and feces (combined) over the 7 day observation period. Independent of the route of administration, the majority of the test substance derived radioactivity was eliminated in the feces (urine: feces ratio 1:2) (Monsanto Co.1991a).

Human information

No quantitative information is available on the extent of absorption and excretion of 4-ADPA in humans. From biological monitoring it is known that 4-ADPA can be detected in the urine and haemoglobin adducts in blood (Bayer AG 2003). Following an accidental dermal exposure to an unidentified amount of the substance, 4-ADPA was detected in the urine of the affected worker (Bayer AG 2003).

Summary and discussion on toxicokinetics

4-Aminodiphenylamine (4-ADPA) can be taken up into the body by the oral and dermal routes of exposure as evidenced by the results of animal studies. About 20 % of the applied dermal dose was shown to be absorbed through the skin, whereas the respective absorption was ca. 80 % of the oral dose In rats the substance and/or its metabolites are eliminated mainly with the feces but can also be detected in the urine. An indirect evidence of dermal absorption in humans is provided by the detection of 4-ADPA in the urine of one worker after single dermal contact with the substance. 4-ADPA can bind to haemoglobin and protein.