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Description of key information

Repeated dose toxicity:
- oral: NOAEL = 684 mg/kg bw/day (70 days feeding study; Analogy CAS 12125-02-9, ammonium chloride)
-oral: NOAEL = 1695.6 mg/kg bw/day (13 weeks feeding study, Analogy CAS 12125-02-9, ammonium chloride)
- inhalative: NOAEC = 262 mg/m3 air (90 days; Analogy 7664-41-7, ammonia, anhydrous)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
684 mg/kg bw/day

Additional information

Oral

For evaluation of oral repeated dose toxicity, a study with ammonium chloride (CAS 12125-02-9) was used for assessment of ammonium hydrogen carbonate. In this subchronic feeding study, ten male Sprague-Dawley received 12300 ppm ammonium chloride (equivalent to 684 mg/kg bw/day) continuously via diet for 70 days (Arnold, 1977). No substance-related effect on clinical signs, body weights, and food consumption or necropsy findings were noted at the end of study. The urine pH was approximately 6.0 compared with a pH of 7.56 or greater in the control group and the concentration of urinary calcium increased. However, crystals in urine were not found. The other urinary chemistries (the concentration of magnesium, creatinine, phosphate, protein, and osmolality) were unchanged. The histopathological examination conducted on stomach kidneys and bladder also did not reveal any substance-related effects. Thus, the NOAEL for repeat dose toxicity was considered to be 12300 ppm equivalent to 684 mg/kg bw/day. Since the ammonium ion is a dissociation product of ammonium chloride similar as it is after dissociation of ammonium hydrogencarbonate, the same result could be expected for ammonium hydrogencarbonate.

In another repeated dose toxicity study for up to 13 weeks, Ammonium Chloride (> 99.5% pure) was administered to 10 Wistar rats/sex/dose in diet at dose levels of 0, 2% and 4% ppm (0, 2200 and 4231.1 mg/kg bw/day; based on food consumption) for 4 weeks and 0, 2.1% and 4% (0, 1695.6 and 3372.5 mg/kg bw/day; based on food consumption) for 13 weeks (Lina et. al., 2004). There were no compound related effects on mortality, clinical signs, or gross pathology either after 4 weeks or 13 weeks of feeding. Food consumption was decreased in the high dose group after 4 weeks and in the initial phases in the 13 week animals. Concomitantly, 4% NH4Cl in the diet resulted in marked and significant (p < 0.01) growth depression at the end of 13 weeks (male 17.3%, female 19.2% below controls). 2.1 % NH4Cl also markedly decreased growth in females (11.1% below control values; p< 0.01). Similar decrease in the body weights of females were seen after 4 weeks of treatment (7.5 % below control value; p < 0.05) treated with 2.1% NH4Cl. NH4Cl induced metabolic acidosis in the rats, as shown by decreases in blood pH, base excess and bicarbonate concentration. The renal contribution to the maintenance of the acid-base state of the blood was reflected in decreased urinary pH and increased urinary net acid excretion. Urinary calcium and phosphorus were increased but the calcium and fat free solid content of the femur were not affected. Histopathology examinations revealed dose related increases in the incidence of zona glomerulosa hypertrophy (adrenals) after 13 weeks (2/20 low dose; 14/20 high dose vs. 1/20 controls) which is ascribed to chronic stimulation of the adrenal cortex by NH4Cl induced acidosis. A slight but no significant increase in the incidence of zona glomerulosa was seen after 4 weeks (2/20 low dose; 3/20 high dose vs. 0/20 controls). The relative weight of the kidneys (relative to body weight) was increased in rats of fed 2.1 NH4Cl (10% above control value; p < 0.05; male only was affected) or 4% NH4Cl (12 - 28%; p < 0.01; both sexes) after 13 weeks but this was not accompanied by a dysfunction of the kidney nor were there any adverse histopathological findings. The NOAEL after 4 weeks is ca. 2200 mg/kg bw/day based on the significant body weight reductions (18-25%) in both sexes of the higher dose animals. The LOAEL (13 weeks) is 3372.5 mg/kg bw/day based on the body weight reduction of up to ca. 20% seen in both sexes of the high dose group. The NOAEL (13 weeks) is thus 1695.6 mg/kg bw/day (Lina et. al., 2004). This subchronic toxicity study in the rats is acceptable for assessment and is comparable to the OECD test guideline (OECD 408) in rats with restrictions (only two test doses were used and the lack of robust results reporting).

 

In the only study on the oral repeated dose toxicity of ammonium hydrogen carbonate, four male albino Wistar rats were given daily 6 mM ammonium carbonate (about 2370 mg/kg bw/d) for 8 days in food (Oliver and Bourke, 1975). The only observed effect induced by ammonium hydrogen carbonate treatment was an increase in the urea level, when compared to control rats, so that the NOAEL was found to be 2370 mg/kg bw/day.

 

Inhalation

Since no study for toxicity after repeated inhalative exposure with ammonium hydrogen carbonate was available, a study with ammonia (CAS 7664-41-7) is shortly described. Read across to ammonia is however not appropriate due to different properties (corrosive vs. not irritating) of ammonia and ammonium hydrogencarbonate.

In this study, 15 Spraque-Dawley and Long-Evans rats were continuously exposed to ammonia for 114 days at 40 mg/m3 and no signs of toxicity were observed. 48 rats were also exposed continuously for 90 days at 127 mg/m3 and 262 mg/m3 (49 rats) and for 65 days at 455 mg/m3 (51 rats).The 127 mg/m3 ammonia exposure had no effects. The exposure at 262 mg/m3 produced only mild nasal discharge in about 25% of the rats. While all rats exposed at 455 mg/m3 showed mild dyspnea and nasal irritation, 32/51 rats were dead by day 25 and 50 were dead by day 65. As result, the NOAEC (systemic) for ammonia was found to be 262 mg/m3. Since ammonia ion is a dissociation product of ammonium hydrogencarbonate with a maximum possible release quantity of 21.5%, roughly calculation with the observed NOAEC value of ammonia would lead to a NOAEC (systemic) of 1219 mg/m3 air for ammonium hydrogencarbonate. Derivation of this NOAEC for ammonium hydrogencarbonate based on the data of ammonia is probably inappropriate for DNEL derivation, as the NOAEC for ammonium hydrogencarbonate is considered to be higher due to different substance properties of ammonia and ammonium hydrogencarbonate.

In the same study, rats, dogs, guinea pigs, rabbits and monkeys were also exposed to 470 mg/m3 ammonia continuously for 90 days. Thereby the observed mortality was 13/15 rats, 4/15 guinea pigs, 0/3 rabbits, 0/2 beagles and 0/3 squirrel monkeys, respectively. The dogs had heavy lacrimation and nasal discharge. There were erythema, discharge and corneal opacity in the rabbits, while there were no hematological effects. The gross necropsies revealed moderate lung congestion in 2/3 rabbits and 1/2 dogs. Histopathology examinations found focal or diffuse interstitial pneumonitis in all animals, as well as epithelial calcification in the renal tubules and bronchi, epithelial proliferation of the renal tubules, myocardial fibrosis, and fatty liver plate cell changes in several of the exposed animals, of each species. Control animals showed less severe similar changes.

 

Livestock

In addition to repeated dose toxicity studies with the preferred animal, the rat, as stated in the OECD test guidelines, feeding studies with livestock animals were available.

One study was conducted to determine the growth rate of Huzhou sheep receiving as their basal diet rice straw alone or rice straw treated with ammonium hydrogen carbonate at 2.7 g/kg bw during 45 days, supplemented with different levels of rapeseed meal (Liu et al., 1998). Since no toxic effect related to ammonium hydrogen carbonate treatment was observed on sheep, the NOAEL was >= 2700 mg/kg.

In another study, up to 3 g/100 g basal diet of ammonium carbonate was given to female chickens in a 14-day feeding study without any effect. The same study found that ammonium was more toxic as the sulphate than as the carbonate salt (Sibbald, 1976). The amount of carbonate converted or previously converted to bicarbonate before feeding could not be revealed. So it is not clear whether there is any difference in sub-chronic toxicity between ammonium as the carbonate salt or bicarbonate salt;

In two other studies, the effects of ammonium hydrogen carbonate on ruminant animals were analyzed (Daugerts, 1962; Wanapat, 1999). The results show an increase in ruminal NH3-content as well digestion and feed rentability.

Read across justification:

Ammonium bicarbonate rapidly dissociates in biological fluids to yield ammonium ion (NH4+) and bicarbonate ion (HCO3-). Ammonium ion then reaches equilibrium with ammonia (NH3) in a pH-dependent fashion and both are integral components of normal metabolic processes and play an essential role in the physiology of man and other species. Bicarbonate ion reaches equilibrium with CO2and H2O in aqueous solution and this equilibrium reaction acts as the major extracellular buffer system in blood and interstitial fluids of vertebrates.

Inorganic salts which are releasing either ammonium or bicarbonate ions are therefore in general suitable as read across substances for ammonium bicarbonate. These substances include: Sodium hydrogencarbonate, ammonium sulphate, ammonium carbamate, ammonium chloride etc.

Justification for classification or non-classification

Classification is not warranted according to the criteria of EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.