Reaction mass of aluminium fluoride and chromium trifluoride and nickel difluoride

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Dose descriptor:

NOAEL

90 mg/kg bw/day

Additional information

No effects on fertility have been observed in a three-generation study in rats using nickel sulfate at dose levels up to 90 mg nickel/kg bw/day (Ambrose et al., 1976). No effects on male or female sex organs in rats and mice have been observed in the 2-year repeat-dose toxicity studies after oral or inhalation administration of nickel sulfate (see section 7.5). Neither histological alterations in male or female reproductive tissues have been observed in rats exposed to 187.5 mg nickel/kg/day as nickel sulfate in the diet for 2 years, or dogs exposed to 62.5 mg nickel/kg/day as nickel sulfate in the diet for 2 years (Ambrose et al., 1976).

In the Ambrose 3-generation study, considered of reliability 2 according to the Klimisch cotation criteria, the potential for effects on sex organs has not been investigated appropriately, as sperm quality and oestrus cyclicity were not part of the examinations. Therefore, to be able to draw clear conclusions regarding the potential for effects on sex organs other studies including these endpoints would be relevant. However, there is no reason to expect that such testing would result in lower NOAELs than the ones already determined for repeat-dose toxicity. Therefore, the results of such testing are unlikely to influence the outcome of the risk assessment.

Short description of key information:
No adverse effects on male or female fertility were detected in a 3-generation feeding study in rats using nickel sulfate at 250, 500 or 1000 ppm (equivalent to 22.5, 45 or 90 mg nickel/kg/day).

Effects on developmental toxicity

Description of key information

No teratogenic effects were detected in a 3-generation feeding study in rats using nickel sulfate at 250, 500 or 1000 ppm (equivalent to 22.5, 45 or 90 mg nickel/kg/day). However, embryotoxicity resulting in a dose-related increase in the number of stillborn pups was observed at all dose levels tested.

Effect on developmental toxicity: via oral route

Dose descriptor:

LOAEL

22.5 mg/kg bw/day

Additional information

There is strong evidence that prenatal exposure to nickel results in decreased survival, as measured by live litter size and neonatal mortality, in pups of rat dams exposed to nickel sulfate in feed prior to mating and during gestation and lactation (Ambrose et al. 1976). Interpretation and comparison with other studies is complicated by differences in study design and maternal toxicity, which often occurs at the same dose levels as the developmental effects. In the Ambrose study however, embryotoxicity was observed at all dose levels, including dose levels not causing maternal toxicity. Decreased pup survival is considered a serious LOAEL.

In this 3-generation study, considered of reliability 2 according to the Klimisch cotation criteria, involving exposure of rats to 0, 22.5, 45, or 90 mg nickel/kg/day as nickel chloride in the diet for 11 weeks prior to mating, during mating, gestation, and lactation, a dose-related increase in the number of stillborn pups was observed. Embryotoxic effects were apparent at all dose levels tested, including the low dose of 22.5 mg nickel/kg/day for the F1a generation. The study authors noted that the number of offspring (dead and alive) was progressively less with increasing nickel levels above 45 mg/kg/day (10.3, 10.6, 9.8, and 9.0 for 0, 22.5, 45, and 90 mg/kg/day, respectively). The number of offspring weaned per litter was also decreased with increasing nickel levels (8.1, 7.2, 6.8, and 6.4 for 0, 22.5, 45, and 90 mg/kg/day, respectively).

In this study, no significant, nickel-related gross abnormalities was observed in the surviving offspring of rats exposed to nickel.

In summary, the animal experimental data provide suggestive evidence that exposure to nickel prior to mating and during gestation and lactation results in decreased survival. Basic assumption is made that after intake nickel compounds are changed and that it is the nickel ion that is the determining factor for the reproductive and developmental toxicity. Different studies have shown that water-soluble nickel salts have the potential to cause embryotoxicity in rodents. The metal can cross the feto-maternal barrier and enter the fetus. The embryotoxicity of nickel may be related to several factors including the mutagenic properties of nickel, direct effects on the mammalian embryo, or indirect effects through maternal toxicity.

The official classification of nickel sulphate, nickel chloride, nickel nitrate and nickel carbonates as Repr. Cat 2; R61 (30^thATP) was made based on the consistent evidence of developmental toxicity (stillbirth, postimplantation/perinatal lethality) in rats at dose levels not causing maternal toxicity.

Justification for classification or non-classification

According to the Annex I of Directive 67/548/EEC, nickel fluoride (CAS No.: 10028 -18 -9) and nickel chloride (CAS No.: 7718 -54 -9) are classified Reprotoxic Category 2; R61 (may cause harm to the unborn child).As they are both present at 9.5 and 4.5% respectively in the mixture, PBN1 mixture should be classified as Reprotoxic Category 2; R61 taking into account the classification criteria of Directive 1999/45/EC (> 0.5%) or Reprotoxic cat. 1B (H360) taking into account the classification criteria of Directive1272/2008/EC (CLP, > 0.3%).