N-(4-aminophenyl)aniline

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Dose descriptor:

NOAEL

435 mg/kg bw/day

Additional information

Effects on fertility

Non-human information

There are no studies available performed according to current guidelines. But on the basis of repeated dose toxicity studies the potential effects of 4-ADPA on reproductive organs of the male rat can be assessed. For the female rat and mice of both sexes useful information can be derived from the cancer bioassay that sufficiently documents histological examination of the reproductive organs and indicates no effects.

In a subchronic toxicity study (Singh 1986 see also chapter repeated dose toxicity) groups of 12 male Wistar rats were exposed to 4-ADPA via the diet (food concentrations of 1000, 2500, 5000 or 7500 ppm 4-ADPA corresponding to approximately 100, 250, 435-500 or 555-750 mg/kg bw/d) for 90 days. Beside the standard parameters (weight gain, food intake, organ weights, haematology and clinical chemistry and macroscopic examination of major organs) also investigations on a possible impairment of reproductive parameters were performed. Weights of testes and accessory sex glands (ventral and dorso-lateral prostates, coagulating glands, seminal vesicles) were determined and serial sections of the left testis were examined microscopically. Furthermore LDH, hyaluronidase and cholesterol in testis, alkaline phosphatase in seminal vehicles, acid phosphatase in ventral prostates and fructose in coagulating glands and dorso-lateral prostates were determined. A marginal depletion (approximately 25 %) of testicular LDH and hyaluronidase at 5000 ppm (approximately 435 to 500 mg/kg bw7d) and 7500 ppm (approximately 555 to 750 mg/kg bw/d) which was statistically significant for the hyaluronidase, pointed to a possible impact on spermatogenesis. A disturbed function of spermatogenesis at 7500 ppm (approximately 555 -750 mg/kg bw/d) can be assumed from the degeneration of seminiferous tubules in testes that was evident at the microscopic examination. There were no multinucleated giant cells and interstitial tissue had normal vascularity and Leydig cells. No histological changes in testes were seen at lower doses. Testes weight as well as other clinical chemical parameters of testes and accessory sex glands was unaffected over the whole dose range. The effects on male reproductive organs were accompanied by a pronounced liver toxicity (see chapter repeated dose toxicity). Systemic toxicity such as slight anaemia was already observed at 250 mg/kg bw/d. In this study the NOAEL for effects on male reproductive organs is 5000 ppm (approximately 435 to 500 mg/kg bw/d) with regard to histopathological changes in the testes. Signs of testicular toxicity are reported after administration of 4-ADPA in doses equal to those which induce histopathological changes in the liver.

The reproductive organs of male and female Fischer rats (prostate/testis and uterus/ovary) were unaffected at dietary doses up to 60 -120 mg 4-ADPA/kg bw/d in the cancer bioassay. The histopathological findings of the cancer bioassay with B6C3F1 mice gave no evidence of 4-ADPA induced alterations in the female and male reproductive organs (prostate/testis and uterus/ovary) up to time-weighted average doses of 8170 ppm and 4114 ppm 4-ADPA in the diet (due to missing data on food consumption a reliable calculation of the applied doses in mg/kg bw/d is impossible) (NTP 1978)

Human information

There are no data available.

Short description of key information:
There is no fertility study available. In a 90-day feeding study (Singh 1986) on male rats, degeneration of seminiferous tubules in the testes, accompanied by marginal changes in enzyme activities (LDH and hyaluronidase) were found at severely toxic dose level (about 7500 ppm, approximately 555-750 mg/kg bw/d). The NOAEL for testicular toxicity was determined as 5000 ppm (approximately 435 to 500 mg/kg bw/d). In early NTP (1978) carcinogenicity studies with rats and mice no histological changes in the reproductive organs of both sexes were observed up to and including the highest dose tested (corresponding to approximately 60 to 120 mg/kg bw/d for the rats; due to severe limitations in the study no reliable dose could be derived for the mice).
Based on the findings of the 90-day feeding study (Singh 1986) which indicate adverse effects on the testes only at high and toxic doses and that demonstrates effects on liver and hematological parameters as most sensitive endpoints it is concluded that there is no evidence of a specific reproductive potential and that the DNEL long-term exposure covers the DNEL fertility.

Effects on developmental toxicity

Description of key information

Developmental toxicity (significant increased resorption, reduced foetal weight and increased foetal anomalies) was observed in two reliable gavage studies on CD rats (Monsanto Co.1989), exposed from gestational day 6 to 15 to doses that caused clear maternal toxicity (>= 100 mg/kg bw/d), as evidenced by significantly decreased weight gain and food consumption. The maternal and developmental NOAELs were identified at 50 mg/kg bw/d.

Effect on developmental toxicity: via oral route

Dose descriptor:

NOAEL

50 mg/kg bw/day

Additional information

Developmental toxicity

Non-human information

The developmental toxicity of 4-ADPA was investigated in CDR rats in two successive studies under identical test conditions.

In the first study, groups of 25 pregnant CDr rats were treated with 4-ADPA by gavage once per day on gestation days 6 to 15 at only a single dose level of 150 mg/kg bw/d. There was one early death (at dosing day 3) in the substance treated group. All 4-ADPA treated dams exhibited clear maternal toxicity evidenced by significantly decreased weight gain (including a weight loss of 7 g from GD 6 to 11 in contrast to a weight gain of 21 g in controls) and significantly reduced food consumption during the entire dosing and post-treatment period (GD 6 to 20). Treated dams also exhibited excessive salivation after dosing and staining of fur in the ano-genital region. No effect of treatment was seen on number of viable foetuses, implantation sites and number of corpora lutea or other uterine implantation data. The mean number of resorption sites per pregnant female, the mean ratio of resorptions to implants and the incidence of females with resorptions among their uterine implants of the treated group did not statistically differ from control animals. However, the increase in resorption data for the treated group was considered to be treatment-related response because the mean number of resorption sites for the treated group (1.7) was outside the range of the recent historical control data (0.3 to 1.1; mean value 0.7). Developmental toxicity was demonstrated by the increase in resorption sites, and a significant decrease in foetal body weights. A significant increase in ossification variations probably reflected a delay in development. Skeletal, visceral and external malformations were significantly increased in the foetuses from treated dams. External malformations included reduction and/or shortening of digits, limbs flexure defects and edema. Discoloration of the snout was also noted. Visceral malformations included ocular defects, abnormal pattern of aortic/pulmonary trunk vessels, distended lateral and third ventricles of the brain, cleft palate, ectopic ovaries and undescended testes. Skeletal malformation included rib defects, vertebral defects, curved scapula and fused maxilla. Many of the findings from the external, skeletal and visceral examinations have been reported in the literature to be associated with maternal toxicity (Monsanto Co. 1989b).

In another developmental toxicity study done by the same laboratory, groups of 24 pregnant CD® rats were exposed to 10, 50 or 100 mg/kg bw/d by gavage from gestational day 6 to 15. Reported clinical signs were excessive salivation in all groups with a dose relationship and in the highest dose group staining of the skin/fur in the anogenital region and soft stool with increasing frequency during the dosing period. At 100 mg/kg bw/d, the weight gain was significantly decreased and the food consumption of dams was 26% lower than that of the controls during early dosing on gestation day 6 to 11. The significant reduction in weight gain and the decrease in food consumption were considered clear signs of maternal toxicity. Mean number of viable foetuses, implantation sites and number of corpora lutea were comparable for the treatment and the control groups. A significant reduction in foetal weights in the high dose animals was indicative of a fetotoxic effect. An increased incidence of skeletal malformations and variations were restricted to the high dose group. The most prevalent findings were wavy ribs, fused ribs, vertebral defects and ossification variations. These findings were considered to be associated with maternal toxicity. At dose levels where no overt toxicity was seen, similar rib and vertebral defects were not seen. The NOAEL both for maternal and developmental effects was 50 mg/kg bw/d (Monsanto Co. 1989a).

In a developmental toxicity study, groups of 11 to 12 pregnant Sprague-Dawley rats were exposed to 4-ADPA by gavage from gestational day 6 to 15 in dosages of 50, 100 or 200 mg/kg bw/d. Maternal body weight gain was significant reduced at 200 mg/kg bw/d during the treatment period, followed by a significant increase after termination of exposure. Data on food consumption were not reported. No other signs of maternal toxicity were found. No adverse developmental effects were seen in the treated groups as compared to the controls. In this study, the NOAELs were determined as 100 mg/kg bw/d for maternal toxicity and 200 mg/kg bw/d (highest tested dose) for developmental effects (Picciano 1984).

Human information

There are no data available.

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).