Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

The key study for reproductive toxicity, including fertility and prenatal/postnatal development was a 2-generation study in Sprague-Dawley rats (Tyl, 2000), which was conducted using dietary exposures of rats to 1,4-benzenediamine, N,N'-mixed Ph and tolyl derivs. at 120, 400, & 1500 ppm (corresponding to approximate doses of 7.5, 25 and 100 mg/kg bw/day in non-pregnant animals and 20, 60 and 240 mg/kg bw/day in pregnant animals) (Tyl, 2000). The study was considered adequate, relevant and reliable as it was conducted according to GLP and OECD 416 test guidelines. Relatively minor effects were observed such as renal polycystic changes at 120 ppm in parental F0 animals and slight increases in relative liver weights in parental F0 & F1 male rats dosed at 1500 ppm, however these were considered to be incidental findings. Reproductive effects included a decreased gestational index in the F0 generation at the high dose only, and a prolongation of gestation in F0 & F1 maternal animals. The number of total & live births per litter on post-natal day 0 was diminished to a degree in all dose groups of the F1 & F2 generations with statistical significance seen in the mid and high dose F1 litters, and high dose F2 litter. These findings were most probably associated with slightly increased (female) pup weights at birth in both generations. The NOEL for female reproductive toxicity including fertility was therefore <120 ppm (or approximately < 7.5 mg/kg bw/day) for the different generations.

No reproductive toxicity however was observed in males due to chemical exposure up to 1500 ppm in both generations, therefore the NOAEL for male fertility was 1500 ppm (or approximately 100 mg/kg bw/day).


Short description of key information:
Influence of 1,4-benzenediamine, N,N'-mixed Ph and tolyl derivs. on fertility and reproductive toxicity were tested in a two-generation study in rats, with dose levels of 120, 400 and 1500 ppm in the diet. No reproductive toxicity was observed in males of F0 & F1 generation up to 1500 ppm, whereas both maternal and reproductive observations were observed at the various dose levels in all generations of female rats.

Effects on developmental toxicity

Description of key information

The key study for developmental toxicity was a teratogenicity study in rats dosed by oral gavage at 20, 70 and 200 mg/kg bw/day (Tyl, 1995).

No embryotoxicity nor teratogenicity were observed up to the highest tested dose level, whereas slight maternal toxicity was seen at 200 mg/kg bw/day.

Additional information

A key prenatal developmental toxicity study was conducted in Sprague-Dawley rats dosed by oral gavage from pregnancy day 6-15 with 1,4-benzenediamine, N,N'-mixed Ph and tolyl derivs. at doses of 20, 70 and 200 mg/kg bw/day in corn oil (Tyl, 1995). The study was conducted according to GLP and OECD 414 test guidelines, and was considered to be adequate, reliable and relevant. Very minimal effects consisting of body weight gain deficits were observed in maternal animals at the highest dose level of 200 mg/kg bw/day, therefore the maternal NOEL was 70 mg/kg bw/day. There were no compound related adverse changes seen in fetuses at any exposure level in this study, therefore the developmental NOAEL was 200 mg/kg bw/day. Postnatal developmental toxicity was studied in the 2-generation toxicity study but did not demonstrate adverse effects in the first and second generation (Tyl, 2000).

Justification for classification or non-classification

Based on the 2-generation study, classification as Reprotox. Cat. 2 is deemed appropriate.

For a detailed assessment of classification and labelling please refer to the attachment in the information panel below.