Ammonium hydrogendifluoride

Carcinogenicity

Description of key information

No studies are available for AMBI.  High quality NTP studies in the rat and mouse are available for the read-across substance, sodium fluoride.  Data are also available for ammonia and ammonium salts.  There is no evidence for carcinogenicity.

Justification for classification or non-classification

No classification is proposed. The EU RAR has reviewed all available data for HF and NaF and concludes that the data are sufficient to suggest that fluoride is not carcinogenic in animals. There is no evidence for the carcinogenicity of ammonium.

Additional information

Justification for read-across from sodium fluoride

There are no carcinogenicity studies available for AMBI. The effects of chronic AMBI exposure will be dominated by local effects at the site of contact (irritation/corrosion), therefore performing studies cannot be supported for scientific reasons and also on animal welfare grounds. Once absorbed into the body, AMBI will dissociate into its constituent ions and systemic toxicity will be due to fluoride. The analogous behaviour of sodium fluoride (or any other water-soluble fluoride salts) means that read-across from NaF to AMBI is scientifically justified.

Studies in the rat: sodium fluoride

The NTP rat study showed evidence of an effect of sodium fluoride administration on the bones and teeth, consistent with the findings of other studies. There was no effect on survival in this study; bodyweights, food and water consumption, haematological and clinical chemistry paramaters and organ weights were unaffected by treatment. Serum, urine and bone fluoride concentrations were increased in all treated groups; the urine calcium concentration was also marginally higher in females at the highest dose level. Osteosclerosis was seen in females at the highest dose level. The incidence of osteosarcoma was increased in males at the intermediate dose level (2%) and the high dose level (4%) but was within the historical range (0 -6%; mean 0.5%). The NTP concluded that the study provides 'equivocal evidence' for carcinogenicity in male rats. An additional carcinogenicity study with NaF in the rat is available (Maurer et al, 1990). No evidence of carcinogenicity was seen in this study, at dose levels sufficient to cause toxicity.

Studies in the mouse: sodium fluoride

The NTP mouse study showed evidence of an effect of sodium fluoride administration on the teeth, consistent with the findings of other studies. There was no effect on survival in this study; bodyweights, food and water consumption, haematological parameters and organ weights were unaffected by treatment. Clinical chemistry revealed elevated ALP activity in females at the highest dose level. Microscopic findings were limited to dentine dysplasia in male mice at 175 ppm. There was no evidence of carcinogencity in either sex. An additional carcinogenicity study with NaF is available (Maurer et al, 1993). A high level of osteosarcomas was seen in all (control and treated) groups in this study, a finding which was attributed to infection with a retrovirus. No conclusion on the carcinogenicity of sodium fluoride can be drawn from this study.

Ammonia studies

Ammonia/ammonium is present in the body as a normal product of metabolism (protein catabolism). It is therefore considered unlikely that this simple molecule is carcinogenic. Nevertheless some data are available and are evaluated.

No evidence of carcinogenicity was seen in a rat dietary study with ammonium sulphate (Otaet al, 2006). The NOAEL for this study was 0.6% (dietary level) equivalent to 256 and 284 mg/kg bw/day in males and females respectively [67 and 74 mg/kg bw/d ammonia equivalents]. In a non-standard mechanistic assay, Tsuji et al (1992) exposed MNNG-initiated rats to 0.01% ammonia solution via drinking water. Gastritis was seen in all animals, indicating a local irritant effect. The incidence of gastric tumours was increased in treated animals, suggesting that ammonia may be acting as a promoter of carcinogenesis. Solutions of hydrazine as 0.001%, methylhydrazine as 0.01%, methylhydrazine sulfate as 0.001%, and ammonium hydroxide as 0.3, 0.2 and 0.1% were administered continuously in the drinking water of 5- and 6-week-old randomly bred Swiss mice for their entire lifetime. Similarly ammonium hydroxide as a 0.1% solution was given to 7-week-old inbred C3H mice. Hydrazine and methylhydrazine sulfate significantly increased the incidence of lung tumors in Swiss mice, while methylhydrazine enhanced the development of this neoplasm by shortening its latent period. The ammonium hydroxide treatments in Swiss and C3H mice were, however, without carcinogenic effect, and did not inhibit the development of breast adenocarcinomas in C3H females, which are characteristic of these animals. The present study thus proves for the first time the carcinogenicity of methylhydrazine, provides further evidence of the tumor-inducing capability of hydrazine by itself and negates the possibility that the metabolite of hydrazine, ammonium hydroxide, could interfere in the development of neoplasia (Toth, 1972).