N-(4-aminophenyl)aniline

Endpoint summary

Description of key information

The NOAEL in a 90-day feeding study with male rats was 1000 ppm (approximately 100 mg/kg bw/d) (Singh 1986). In this study, slight anemia, and changes in liver enzyme levels were seen at approximately 250 mg/kg bw/d (2500 ppm). At 5000 ppm (approximately 435 - 500 mg/kg bw/d) pathological changes in the liver were found at the histological examination, and at 7500 ppm (approximately 555- 750 mg/kg bw/d) histopathological changes were found in the testes (degeneration of seminiferous tubes). The NOAEL in a rat carcinogenicity study with dietary exposure over 78 weeks was 1200 ppm (approximately 60 -120 mg/kg bw/d; highest dose tested). Based on the findings from the 90 day feeding study (Singh 1986) and the supporting results from the carcinogenicity study, the NOAEL for repeated dose toxicity is assessed to be 100 mg/kg bw/d.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Additional information

Repeated dose toxicity: oral

There are no studies available performed according to current guidelines. However, information concerning repeated dose toxicity of 4-ADPA is available from 7-week studies in rats and mice, from a 90 day study which involved only male rats and from two limited carcinogenicity studies with 78-week feeding of 4-ADPA to rats and 48-week feeding to mice.

In range-finding studies for the cancer bioassays (examined parameter mortality and body weight gain) Fischer 344 rats and B6C3F1 mice (5 males and 5 females/dose group) were orally exposed to 4-ADPA for 7 weeks. Concentrations in the food were 2200, 3200, 4600 and 10000 ppm (approximately 220, 320, 460, 680, 1000 mg/kg bw/d) for rats and 3000, 4400, 6500, 9500, 14700, 21600 or 31500 ppm (approximately 450, 660, 975, 1425, 2205, 3240, 4725 mg/kg bw/d) for mice (NTP 1978). Rats responded with a significant dose-dependent reduction in body weight gain at doses > 2200 (approximately 220 mg/kg bw/d; males 7 2%, females 50 % of controls). Mortality was increased at the two highest doses of 6800 ppm and 10000 ppm (approximately 680 and 1000 mg/kg bw/d). Mice showed no increased mortality in both sexes and unaffected body weight gain in males up to the highest dose of 31500 ppm (approximately 4725 mg/kg bw/d). Weight gain was decreased in female mice at > 14799 ppm (approximately 2205 mg/kg bw/d; no further details available (NTP 1978).

In a 90-day study, groups of 12 male Wistar rats were orally exposed to dietary concentrations of 1000, 2500, 5000 or 7500 ppm 4-ADPA (approximately 100, 250, 500 (435), 750 (555) mg/kg bw/d). No information is given with regard to mortality and clinical signs. For the two highest doses only a decrease in body weight gain (11.7% at 5000 ppm, 0% at 7500 ppm in comparison to 36% in controls) in parallel to a reduced food intake was described (decrease of 13% at 5000 ppm and 26% at 7500 ppm corresponding to calculated doses approximately 435 and 555 mg/kg bw/day). Consistent haematological changes observed at > 2500 ppm (approximately 250 mg/kg bw/d; reduction of numbers of erythrocytes and haemoglobin, increased MCV) suggest haemolytic anaemia. A significant decrease of the hematocrit value (PCV) was noted at 7500 ppm. Unchanged organ weights and no findings in microscopic examination of stomach, intestine, heart, lung, spleen, adrenals and kidneys as well as unchanged accessory sex gland weight revealed no adverse effects to these organs. Hepatotoxicity was evident from increased liver weight (35% both at 5000 and 7500 ppm) and changes in marker enzymes in serum at > 2500 ppm (approximately 250 mg/kg bw/d). Histopathological findings as degenerative changes of hepatocytes from 5000 ppm (approximately 435-500 mg/kg bw/d) and plasma cell reaction in portal triad area also showed a hepatotoxic effect of 4-ADPA, whereas the livers presented normal appearance at doses of 2500 ppm and lower. At 7500 ppm (approximately 555-750 mg/kg bw/d) degeneration of seminiferous tubules in testes as well as decreased hyaluronidase activity in testes which started at 5000 ppm (approximately 435 - 500 mg/kg bw/d) were described. There were no multinucleated cells and interstitial tissue had normal vascularity and Leydig cells. No histological damage was seen at lower doses and testes weight was unaffected over the whole dose range (Singh 1986). For the 90-day feeding of 4-ADPA to male rats a NOAEL of 1000 ppm, corresponding to a dose of approximately 100 mg/kg bw/d is derived with regard to haematology parameters and changes in liver enzymes as first indication of an impact on this organ (Singh 1986).

In a carcinogenicity study male and female Fischer rats (50 of each sex/dose group; 20 per sex in the control group) were exposed to concentrations of 600 ppm (approximately 30-60 mg/kg bw/d) or 1200 ppm (approximately 60-120 mg/kg bw/d) via diet for 78 weeks and were killed after further 26 weeks. The study protocol comprised observation of mortality, clinical signs, body weight and macroscopic examination as well as macroscopic and microscopic examination of all major tissues and organs. There were no significant adverse effects on survival or body weight and no clinical signs of intoxication in any of the 4-ADPA exposed groups. Gross pathology and histopathology revealed no substance related changes. For these endpoints the NOAEL was 1200 pm corresponding to 60 to 120 mg/kg bw/d (NTP 1978).

The low toxicity that was observed in the dose range-finding study in mice (see above, up to 31500 ppm, approximately 4724 mg/kg bw/d), only mean body weight gain depression was recorded for female mice) was not confirmed by the findings of the carcinogenicity study because both dose levels and exposure periods had to be reduced for mice due to pronounced toxicity. 50 B6C3F1 mice of each sex per dose group were initially dosed via the diet with 2500 or 5000 ppm (males) or with 5000 ppm and 10000 ppm (females). However, these concentrations were lethal in particular for the female mice which died with signs indicative of a central nervous system disturbance (not further specified) so that the dosing scheme had to be changed at week 31. Male mice were exposed to 1250 or 2500 ppm for further 17 weeks. Low dose females received 1250 ppm for further 17 weeks; the exposure of the high dose group females was first completely interrupted for 7 weeks followed by a dose of 2500 ppm for further 10 weeks. Time weighted averages for the 48-week dosing period were 2057 and 4114 ppm for the male mice and 3672 and 8170 ppm for female mice (due to missing data on food consumption a reliable calculation of the applied doses is impossible). The surviving animals were killed 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 occurred from week 22-40 in males and week 8-46 in females. The terminal survival in control, low- and high-dose groups was 85, 94 or 88% in males and 85, 68 or 58% in females. 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, or 48 %; females: 5, 16 or 4%). However, limitations of this study are the obviously highly toxic initial doses requiring the reduction of doses in all 4-ADPA-exposed groups. Therefore, only limited conclusions can be drawn from this study pointing to the liver as possible target organ of 4-ADPA in mice (NTP 1978).

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).