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Carcinogenicity

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Description of key information

Ammonium carbamate is negative for causing cancer in rats and mouse (analogue approach; sodium bicarbonate and ammonium chloride).

Key value for chemical safety assessment

Justification for classification or non-classification

Based on available data there is no need for classification according to EU Directive 67/548/EEC and the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.

Additional information

A broad base of literature data and the results of hydrolysis studies performed by the registrant indicate that ammonium carbamate rapidly decomposes into ammonium and carbonate/bicarbonate at physiological concentrations and pH (see rationale in chapter 5.1.3).

Due to the lack of data on carcinogencity for ammonium carbamate, studies performed with sodium bicarbonate (CAS# 144-55-8) and ammonium chloride (CAS# 12125-02-9) were used for assessment since ammonium carbamate will dissociate in biological fluids like blood (pH 7.34-7.45) to NH4+and CO32-ions.

In a feeding study, male Fischer 344 rats were presented diets supplemented with 0.64% NaHCO3 (6400 ppm) continuously for 104 weeks (Fukusima et al, 1989). The liver, kidney and bladder were examined histologically. Although the survival rate was not decreased, the final body weight of the exposed male rats was lowered compared to the control. The NaHCO3 exposed animals did not have a significant increase in the number of tumours. Papillary or nodular hyperplasia and papillomas incidences did not differ from that of the control group. Although only males were used for testing, sodium bicarbonate was found to be not carcinogenic.

In 30 month feedings study, ammonium chloride (>99.5% pure) 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) (Lina et al, 2004). 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 compound related effects in 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. The zona glomerulosa was distinctly wider than in controls; the cells in this area were enlarged and showed a finely vacuolar cytoplasm. Early increases (after 4 and 13 weeks) in zona glomerulosa hypertrophy were also noted with the high (4%) level of NH4Cl (see Section on repeated dose toxicity). This effect is considered to be caused by the chronic stimulation of the adrenal cortex by NH4Cl induced acidosis and as such is not regarded as adverse.

With 2.1% NH4Cl, the incidence of oncocytic tubules was significantly decreased after 30 months. The oncocytic tubules were characterised by tubules lined with, often hypertrophic, epithelial cells containing eosinophilic granular cytoplasm (oncocytes). The oncocytic tubules often showed a cystically dilated lumen with epithelial cells protruding into the lumen. 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, while the qualification "very severe nephrosis" did not occur in this group. The NOAEL for toxicity is 2.1% (1104.6 mg/kg bw) NH4Cl in diet.

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% NH4Cl in diet. This carcinogenicity study in the rats is acceptable and satisfies the guideline requirement for a carcinogenicity study OECD 451 in rats.

 

In a mouse study, treatment for 50 female (1F X C57/F1) mice/dose, 7 days/week for 652 days with 1% ammonium chloride (no data on purity) in drinking water did not cause any tumours in the bladder. Neither was there any epithelial hyperplasia or calculi found in the bladder. The average survival time was 492 days (control: 485 days) (Flaks and Clayson, 1975).

 

Taken together, the above data not only show that ammonium chloride is not carcinogenic but rather seem to possess anticarcinogenic potential. Lina et al (2004) proposed the reduction of systemic pH as a possible mechanism for the apparent anticarcinogenic potential of NH4Cl. In an initiation/promotion study reported by Higiwara et al (1994), the incidence of hyperplasia and papillomas were reduced in male Fisher 344 (DuCrj) rats (no data on age) after a 32 week administration via feed of 1% ammonium chloride (no data on purity). Prior to treatment with ammonium chloride, the test animals were treated with 0.05 % (N-butyl-N-(4-hydroxybutyl) nitrosamine for 4 weeks. The control animals were given non supplemented diets after the 4 week tumour induction phase.