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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Description of key information

Comprehensive repeated dose oral toxicity data are available for sodium fluoride and for ammonia.  AMBI will dissociate under physiological conditions to form fluoride and ammonium ions.  The effects of repeated exposure to AMBI at high concentrations will be dominated by local corrosivity and irritation.  Ammonium is of relatively low sytemic toxicity, therefore the critical systemic toxic effects of AMBI will be due to fluoride.

Key value for chemical safety assessment

Additional information

No data are available for AMBI, however comprehensive read-across data are avaialable for other soluble inorganic fluoride salts, ammonia and ammonium salts.

Read-across data for fluoride compounds

Repeated dose oral toxicity

No studies have been performed with the substance, however comprehensive data are available for the read-across substance sodium fluoride. The repeated dose oral toxicity of ammonium hydrogendifluoride and NaF are considered to be essentially identical, with the exception of likely irritant/corrosive effects of ammonium hydrogendifluoride at high dose levels. With the exception of corrosivity, the repeated dose oral toxicity of ammonium hydrogendifluoride will be due to fluoride, therefore read-across from the comprehensive NTP dataset with the soluble salt NaF is appropriate.

In a 14 -day range-finding study with NaF in the rat, mortality was seen at drinking water concentrations of 400 and 800 ppm. Signs of toxicity (reduced weight gain, reduced water consumption, lethargy and dehydration) were noted in surviving animals in these groups. The NOAEL for this study was 200 ppm. In a 14-day range-finding study in the mouse, mortaility was seen at the highest dose level of 800 ppm; signs of toxicity (reduced weight gain, abnormal gait and posture, reduced water consumption) were also apparent at this dose level. A NOAEL of 400 ppm is determined for this study. In a 6 -month rat study, the effects of exposure to NaF were limited to reduced weight gain, dental fluorosis, thickening and ulceration of the gastric mucosa at the highest dose level of 300 ppm; gastric effects were also seen at 100 ppm. The fluoride content of plasma, bone and teeth increased with dose levels. The NOEL for this study was 30 ppm, however these local effects are not considered to be relevant for the risk assessment therefore a NOAEL of 100 ppm can be determined. In a 6 -month nouse study, mortality attributable to acute nephrosis was seen at the highest dose level of 600 ppm. Skeletal effects were seen in males at the lowest dose level of 50 ppm.

Repeated dose dermal toxicity

No studies are available. The effects of dermal exposure will be dominated by local irritation / corrosion. There is no evidence of significant dermal absorption of AMBI under exposure conditions where the integrity of the skin barrier is maintained. Testing for repeated dose dermal toxicity can therefore be waived on scientific grounds and for reasons of animal welfare. The effects of repeated inhalation exposure to the read-across substance hydrogen fluoride (HF) have been adequately characterised; the effects of repeated exposure to fluoride are also well characterised.

Repeated exposure inhalation toxicity

In a published study (Sadilova et al, 1974), female rats were exposed to 1 mg/m3 HF 6 hours/day for 1 month. Effects were noted on the teeth, bones and respiratory tract. Two proprietary studies (Placke et al; 1990, 1991) are summarised in the EU RAR, however the data owner is unknown and therefore there is no access to these studies. The EU RAR summary states an overall NOAEL for repeated inhalatory exposure in male and female rats was identified as 0.72 mg/m3(actual HF concentration) for a 6 hours per 5 days per week for 91 days exposure regimen. No adverse effects were noted at this concentration. At higher concentrations death, tissue irritation, dental malformations, haematological and biological changes and changes in several organ weights were observed.

Summary

Effects of repeated fluoride exposure in experimental animals were seen on the teeth, bones, respiratory tract and kidney. Evidence from epidemiological studies in humans also indicate that prolonged exposure to fluoride causes dental and skeletal effects.

Read-across data for ammonia and ammonium compounds

Repeated dose oral toxicity

A 90 -day study in the rat with ammonium sulphate showed only minor effects at high dose levels (diarrhoea, renal pathology); a NOAEL of 886 mg/kg bw/d was determined, equivalent to 225 mg/kg bw/d ammonia (Tagaki et al, 1999). A NOAEL of 256 mg/kg bw/d (equivalent to 67 mg/kg bw/d) was determined for 1 -year and 2 -year studies by the same group (Ota et al, 2006).

Repeated dose dermal toxicity

No data are available.

Repeated exposure inhalation toxicity

A number of non-standard studies of various duration and in different species are available. The data indicate that the primary effect of exposure to inhaled anhydrous ammonia is local irritation of the respiratory tract. In a 5-week study in pigs, ammonia concentrations had a highly significant adverse effect upon feed consumption and average daily weight gain. However, there was no significant effect upon efficiency of food conversion. During both trials the high ammonia levels appeared to cause excessive nasal, lacrimal and mouth secretions. This was more pronounced at 100 and 150 ppm than at 50 ppm. Autopsies carried out on three animals showed no significant gross or microscopic differences related to ammonia level. Cultures of Corynebacterium and Pasteurella were obtained from swabs of the ethmoid turbinates from two animals removed from the compartment maintained at 150 ppm and one animal maintained at 100 ppm. There was no evidence of these bacteria in turbinate swabs from other animals (Stombaughet al, 1969). Sherman and Fischer rats were exposed to environmental ammonia, derived from natural sources for 75 days, or to purified ammonia for 35 days. Rats were either inoculated intranasally with M. pulmonis prior to exposure, or left untreated. The average ammonia concentrations were 105 mg/m3for 75 days and 175 mg/m3for 35 days exposure. Ammonia exposure (from either source) significantly increased the severity of the rhinitis, otitis media, tracheitis and pneumonia (including bronchiectasis) characteristic of murine respiratory mycoplasmosis (rats infected withM. pulmonis). The prevalence of pneumonia showed a strong tendency to increase directly with environmental ammonia concentration (Brodersonet al,1976). Twenty seven male rats, along with 27 age and weight matched controls, were exposed to atmospheric ammonia gas at a concentration of 350 mg/m3for up to 8 weeks. The rats were sacrificed after different exposure times. Nasal irritation began on the fourth day. After 3 weeks continuous exposure exposed rats showed nasal irritation and inflammation of the upper respiratory tract. The number of pulmonary alveolar macrophages was similar to that in the controls. After 8 weeks none of the inflammatory lesions were present (Richardet al,1978). Weatherby (1952) exposed twelve male guinea pigs (plus 6 controls) were exposed to anhydrous ammonia gas for up to 18 weeks (6 hours per day, 5 days per week). The average concentration in air was 119 mg/m3. Four experimental and 2 control animals were sacrificed at 6 week intervals throughout the study. There were no significant findings at necropsy after 6 and 12 weeks exposure. In animals sacrificed after 18 weeks, there was mild congestion of the liver spleen and kidneys, with degenerative changes in the adrenal glands, and hemosiderosis in the spleen indicating hematotoxicity. There was cloudy swelling in the epithelium of the proximal tubules of the kidney as well as albumin precipitation in the lumen with some casts.

In a 50-day study (Stolpe & Sedlag, 1976), male Wistar rats were exposed to two concentrations of ammonia gas, continuously for 50 days. Concurrent controls remained untreated. There was no mortality at either concentration (35 or 63 mg/m3), and no treatment-related clinical effects were observed. Body weight gain and food intake, as compared to control values, was not significantly affected by ammonia exposure. At 63 mg/m3rats showed increased haemoglobin and haematocrit levels compared to controls. The NOAEC was 35 mg/m3

Conclusion of read-across studies

AMBI will dissociate under physiological conditions to form fluoride and ammonium ions. The effects of repeated exposure to AMBI at high concentrations will be dominated by local corrosivity and irritation. Ammonium is of relatively low systemic toxicity, therefore the critical systemic toxic effects of AMBI will be due to fluoride.


Repeated dose toxicity: via oral route - systemic effects (target organ) other: bone

Repeated dose toxicity: inhalation - systemic effects (target organ) respiratory: other; other: bone

Justification for classification or non-classification

No classification is proposed.