Ammonium hydrogendifluoride

Endpoint summary

Additional information

Genetic toxicity in vitro

No evidence of mutagenicity was seen in a guideline-compliant GLP Ames test performed with AMBI (Herbold, 1988). No evidence of mutagenicity was seen with sodium fluoride in an Ames test (NTP, 1990). No evidence of mutagenicity was seen in a mammalian cell mutation assay (V79/HPRT) with sodium fluoride. This study was performed only in the absence of metabolic activation, however this deviation is not considered to be critical as the test substance is not metabolised. A positive result with sodium fluoride is reported in a mouse lymphoma assay (NTP, 1990). Sister chromatid exchage and chromosomal aberrations are reported in an additonal NTP study performed with sodium fluoride.

No evidence of mutagenicity was seen in a guideline-comparable Ames test performed with anhydrous ammonia (Shimizu et al,1985). Similarly, there was no evidence of mutagenicity in a non-standard study using E. coli (Szybalski, 1958)

Genetic toxicity in vivo

Gerdes (1971) reports a marginally (but not statistically significant) postive response to HF in a study in Drosophila melanogaster; positive effects in Drosophila are also reported by Mohamed et al (1971). The significance of these results is unclear; the EU RAR for HF considers the findings of these two Drosophila studies to be inconclusive. Zeiger et al (1994) report no evidence of clastogenicity, even at dose levels caucing severe toxicity, in a well-conducted mouse study performed with sodium fluoride in which chromosomal aberrations and micronucleus formation was assessed. In contrast, a poorly reported inhalation exposure study performed with HF (Voroshilin et al, 1975) reports clastogenicity in the bone marrow of exposed rats but no dominant lethal effect in exposed mice. No evidence of an increase in the incidence of micronucleated polychromatic erythrrocytes was seen in a mouse micronucleus assay performed with the read-across compound ammonium chloride (Hayashi et al, 1988).

Conclusion

The EU RAR concludes that, while the dataset on the genotoxicity of the read-across substance HF is limited, studies with sodium fluoride are also informative as for all substances target tissues will exposed to fluoride (either free or bound to organic molecules). The EU RAR therefore reviews the available data for NaF and HF and concludes that fluoride does not interact directly with DNA and is not genotoxic when administered via an appropriate route (i.e. by oral or inhalation exposure).

Ammonia is a simple molecule and does not possess any structural alerts for genotoxicity. Ammonia is present at relatively low levels in the systemic circulation as a consequence of protein catabolism (largely in the liver) and is also present at higher levels in the hepatic portal circulation due to the breakdown of urea by gastrointestinal bacteria. The ubiquitous presence of ammonia in the leads to the conclusion that it is unlikely to be genotoxic. The WHO evaluation (EHC 54, 1986) concludes that there is no evidence that ammonia is mutagenic in mammals. A UK Health Protection Agency (HPA) evaluation similalry concludes that ammonia does not have significant mutagenic potential.

Short description of key information:
No evidence of mutagenicity was seen in an Ames test performed with AMBI or with the read-across substance HF. A positive result is reported in a mouse lymphoma assay performed with the read-across substance sodium bifluoride (sodium hydrogenfluoride). A number of studies performed with the read-across substance sodium fluoride are also presented. Genotoxicity data for HF and NaF have been reviewed in the EU RAR for HF: it was concluded that fluoride does not interact directly with DNA and is not genotoxic when administered via an appropriate route (i.e. by oral or inhalation exposure).

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

No classification is proposed. The available data indicate that fluoride does not interact directly with DNA and is not genotoxic when administered via an appropriate route (i.e. by oral or inhalation exposure). Ammonium is not considered likley to be genotoxic. I can therefore be concluded that AMBI is not genotoxic.