4-methyl-m-phenylenediamine

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

LOAEL

5.9 mg/kg bw/day

Additional information

For 2,4-TDA valid long-term feeding studies in rats and mice are available.

Dietary exposure of 2,4-TDA to rats at 5.9 mg/kg bw/day (time-weighted average dose after reduced in food from 125 to 50 ppm) for up to 103 weeks caused a clearly dose related delay of body weight gain and dose related decreased survival rates. At >= 5.9 mg/kg bw/day, hepatotoxic effects, and the development of chronic renal disease were seen, an effect that contributed to a marked decrease in survival of dosed rats. Hepatotoxic effects were shown as focal necrosis of hepatocytes to severe, diffuse, toxic degenerative lesions in the liver (>= 5.9 mg/kg bw/day, long-term study; NCI 1979, Cardy 1979). Kidney lesions were observed in both sexes (most marked in males) at >= 5.9 mg/kg bw/day. Corresponding to the renal disease was a high incidence of associated secondary hyperparathyroidism in dosed males (long-term study; NCI 1979). In addition, hepatocellular carcinomas or neoplastic nodules occurred at incidences that were dose related in both male and the female rats (NCI 1979, Cardy 1979). Experimental

data from rat studies demonstrated that 2,4-TDA induced serious health effects consisting of testicular atrophy at 28 mg/kg bw/day for 15 months (Stula & Aftosmis 1976).

The mouse was less sensitive to 2,4-TDA than rats. Mice exposed to dietary levels of 100 ppm (15 mg/kg bw/day) of 2,4-TDA for 101 weeks showed no significant differences in survival compared to the control animals. There was, however, a delay of body weight gain of 25-50%. This effect was dose related except for the low-dose male mice, for which mean body weights were only slightly lower than those of controls. In treated mice, the incidence of hepatic lesions was not increased, and there were no treatment-related findings in the kidneys. Female mice fed 100 or 200 ppm (approx. 15 or 30 mg/kg bw/day) 2,4-TDA for 101 weeks developed a significant number of carcinomas of the liver. Treated mice of both sexes also developed hyperplastic nodules in the liver, but degenerative effects were not observed in mice ingesting 2,4-TDA up to 101 weeks (NCI 1979, Reuber 1979).

For 2,4-TDA a LOAEL of 5.9 mg/kg bw/day (time-weighted average dose after reduced in food from 125 to 50 ppm) was derived from the 2-year feeding study in rats (NCI 1979). A NOAEL was not estimated. Although this long-term feeding study was not in full agreement with the requirements needed for the base set studies of existing chemicals (only two doses tested, no data on haematology and clinical chemistry parameters), it represents the lowest effect level at which relevant toxic effects were observed. At this dosage there were a decreased survival rate, a clear delay in body weight gain, lesions of the liver and kidneys as well as tumors in the liver in high incidences.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver; urogenital: kidneys