N-(4-aminophenyl)aniline

Carcinogenicity

Description of key information

Early feeding studies in rats and mice revealed no evidence of carcinogenicity but these studies have limitations; mainly because of the shortened period of administration of the test substance, i.e. only 78 weeks in rats and 41-48 weeks in mice, respectively. No evidence of a carcinogenic potential was also seen in two dermal carcinogenicity studies, in which a 1% mixture of 4-ADPA was tested.

Justification for classification or non-classification

Based on the findings discussed above no classification is required according to the classification criteria 67/548/EWG and regulation no. 1272/2008 (GHS).

Additional information

Non-human information

Carcinogenicity: oral

Male and female Fischer rats were exposed through the diet for 78 weeks to concentrations of 600 ppm (approximately 30 - 60 mg/kg bw/d) or 1200 ppm (approximately 60 - 120 mg/kg bw/d) and were sacrificed after further 26 weeks. There were no adverse effects on survival or body weight and no clinical signs of intoxication in 4-ADPA-exposed rats. Gross pathology and histopathology neither revealed substance related changes nor increased tumour incidences (NTP 1978). However, limitations of this study are the exposure period restricted to 78 weeks and the absence of distinct systemic toxic effects in the high dose animals.

In the mouse study, B6C3F1 mice were initially dosed with 2500 and 500 ppm (males) or with 5000 and 10000 ppm (females). However, these concentrations were toxic (central nervous effects, hepatotoxicity, decreased body weight, deaths), so that the dosing scheme had to be changed at week 31. Male mice were then exposed to 1250 and 2500 ppm for further 17 weeks. Females of the low dose group received 1250 ppm for further 17 weeks. The exposure of high dose females was first completely interrupted for 7 weeks followed by feeding of 2500 ppm 4-ADPA for further 10 weeks. Time weighted average doses for the total 48-week dosing period were 2057 and 4114 ppm for males and 3672 and 8170 ppm for female mice (due to missing data on food consumption the reliable calculation of the applied doses is impossible). The surviving animals were sacrificed in week 91. Body weight was lowered in all treatment groups starting from week 12 (males up to 15% and females up to 20 % reduction). Premature deaths (especially in females) were attributed to central nervous disturbances (not further specified) and occurred from week 22 - 40 (males) and week 8-46 (females). The terminal survival was 85, 94 and 88 % in males and 85, 68 and 58% in females, respectively. Gross pathology and histopathology revealed exposure-related changes in the liver only. Increased incidences of inflammatory changes were observed in mice of both sexes with a greater sensitivity in males (males: 0, 47 and 48 %; females: 5, 16 and 4%). In male mice the incidence of hepatocellular adenomas or carcinomas was significantly higher in the low dose group compared to controls (males: 10, 37 and 20%; females: 5, 4, and 2%), but there existed no dose related trend and no significant effect compared to historical control data of male mice (53/340 [16%] with a maximum of 7/20 [35 %) at this laboratory. However, limitations of this study are the obviously highly toxic initial doses requiring the reduction of doses in all 4-ADPA-exposure groups. Furthermore, exposure periods were shortened to 48 weeks and 41 weeks (high dose females) and the total study period was reduced to 91 weeks. Therefore, no conclusion on the carcinogenic potential of 4-ADPA in mice can be drawn from this study (NTP 1978).

Carcinogenicity: dermal

No data for the pure test substance are available. However, a mixture of 4-ADPA and hydrogen peroxide were tested in rats and mice. Male and female Sprague Dawley rats were tested in a combined multigeneration study and carcinogenicity study with a mixture of 4-ADPA (1%) and hydrogen peroxide (mixture: 0.5 ml of a solution containing 2% 4-ADPA, prior to mixing an equal volume of 6% hydrogen peroxide). The animals were treated topical with this mixture for 114 weeks. No increase tumour incidences were found in any of the tissues examined (Burnett 1988). In addition, in a study with Swiss-Weber mice, which were topically treated with a mixture of 4-ADPA (1%) and hydrogen peroxide for 21 months, no statistically significant differences in the distribution of tumours among treated and control groups were noted (SCCP 2007).