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Carcinogenicity

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Description of key information

Carcinogenicity:
- oral: negative; NOAEL >= 6400 ppm (104 weeks; Analogy CAS 144-55-8, sodium hydrogencarbonate)
-oral: negative; NOAEL >= 1104.6 mg/kg bw/day (30 months; Analogy CAS 12125-02-9; ammonium chloride)

Key value for chemical safety assessment

Additional information

Due to the lack of data on genetic toxicity in vivo, a study with sodium bicarbonate (CAS 144-55-8) is taken into account for assessment. In this study, male Fischer 344 rats were fed with 0.64% NaHCO3 (6400 ppm) in the diet and they were exposed for 104 weeks (, 1989). The liver, kidney and bladder were removed after gross examination, fixed and used for histological examination. Although the survival was not decreased, the final body weight of the exposed male rats was lower compared to the control. However, the NaHCO3 exposed animals did not have a significant increase in the number of tumors. Papillary or nodular hyperplasia and papilloma incidence did not differ from the control group incidence. Although only males were used for testing, sodium bicarbonate was found to be not carcinogenic. Since the hydrogencarbonate ion is a dissociation product of sodium hydrogencarbonate similar as it is after dissociation of ammonium hydrogencarbonate, the same result could be expected for ammonium hydrogencarbonate.

This view is also supported by the likewise long history of safe use in humans.

In 30 month feedings study with the analogous substance Ammonium Chloride (> 99.5% pure), the substance was administered in diet continuously to fifty (5 week-old) Wistar rats/sex/dose at two doses: namely 1.0 % and 2.1 % for a duration of 30 months (ca. 131 weeks). The control group was presented non supplemented diets. No treatment-related abnormalities in condition or behaviour were observed in the rats of this study. The clinical effects noted were of random nature and corresponded to the usual ageing symptoms seen in this strain of rats. There were also no adverse compound related effects on mortality, food consumption, haematology, clinical chemistry, urinalysis, organ weights. The type and incidence of palpable masses noted during the chronic studies did not indicate any treatment-related effects. Body weights were significantly reduced at various periods over the 30 month study period in females of the low dose group and both sexes of the high dose group. Histopathology examinations revealed dose-related increases in the incidence of zona glomerulosa hypertrophy in all treatment groups in both sexes at the end of the 30-month study. Zona glomerulosa was however not associated with increased blood potassium concentration or increased potassium excretion. Early increases (after 4 and 13 weeks) in zona glomerulosa hypertrophy were also noted with the high (4%) level of NH4Cl (see chapter 7.5.1). With 2.1% NH4Cl, the incidence of oncocytic tubules was significantly decreased after 30 months. The overall incidence of nephrosis was comparable among the groups throughout the studies, but after 30 months the incidence of severe nephrosis was decreased in males of the 2.1% NH4Cl group. The NOAEL for toxicity is 2.1% NH4Cl (1104.6 mg/kg bw).

At the doses tested, there were no treatment-related increases in the incidence or changes in any specific tumour type among the groups. The relatively high incidences of (adeno)carcinomas found in the mammary gland of females treated with 2.1% NH4Cl, were not considered treatment related because these changes were not accompanied by pre-neoplastic alterations in the 18- and 30-month studies and because their incidences were within the range of historical control data. The NOAEL for carcinogenicity is 2.1% (1104.6 mg/kg bw) NH4Cl in diet. This carcinogenicity study in the rats is acceptable and satisfies the guideline OECD 451 requirement for a carcinogenicity study in rats.

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.