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Administrative data

Description of key information

No data is available on repeated dose toxicity for ammonium carbamate. An assessment has been performed using data from ammonium chloride (CAS# 12125-02-9) and ammonium hydrogencarbonate (CAS# 1066-33-7). In a 90 day study with rats, a NOAEL of 1695.6 mg/kg bw/day was achieved. In a study with gaseous ammonia, using different species, a NOAEL of 262 mg/m3 was established for rats, using continuous (24 hr/day) exposure for 90 consecutive days, based on mortality at the next dose level. 

Key value for chemical safety assessment

Additional information

There are no data available on repeated toxicity testing with ammonium carbamate. Analytical data show that ammonium carbamate hydrolyzes at physiological pH in aqueous media according to the following overall equilibrium:

H2NCOO-(aq) + H2O(l) ↔ CO32-(aq) + NH4+(aq) ↔ HCO3-(aq) + NH3(aq)

This equilibrium is well-described in the literature and has been confirmedby13C{1H}-NMR spectrometry at different pH values. For detailed rationale, see endpoint summary for “Toxicokinetics, metabolism and distribution” in chapter 5.1.3. The toxicological properties of ammonium carbamate can be predicted from its dissociation products. As a result, a read-across approach using data from ammonium chloride (CAS No. 7783-20-0) and ammonium hydrogencarbonate (CAS No. 1066-33-7) is considered applicable to cover this endpoint. This strategy is in accordance with section 1.5 of Annex XI of the REACH Regulation.

In a 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) for 4 weeks and 0, 2.1% and 4% (0, 1695.6 and 3372.5 mg/kg bw/day) for 13 weeks (Lina, B.A.R. and Kuijpers, M.H.M, 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, body weights were significantly reduced after 4 and 13 weeks respectively in the high dose animals. In the low dose, body weights of females were also reduced. 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). Relative kidney to body weights were increased both in the 4 and 13 week studies but this was not accompanied by a dysfunction of the kidney nor were there any adverse histopathological findings. The NOAEL after 4 weeks is 2200 mg/kg bw/day, based on the significant reduction of the body weight in the high-dose animals. The LOAEL (13 weeks) is 3372.5 mg/kg bw/day based on the increased incidence of zona glomerulosa hypertrophy (adrenals) and statistically significant decreases of body weights in the high-dose group. However, the former effect is considered to be caused by chronic stimulation of the adrenal cortex by NH4Cl induced acidosis and as such is not regarded as adverse. The NOAEL (13 weeks) is thus 1695.6 mg/kg bw/day (Lina, B.A.R. and Kuijpers, M.H.M, 2004). This subchronic toxicity study with rats is acceptable for assessment and is comparable to OECD test guideline 408 in rats with restrictions (only two test doses were used and the lack of robust results reporting).

In another study with NH4Cl, a group (10 animals/group) of 4-5 weeks old, male Sprague Dawley rats were fed a diet containing 0 and 12300 ppm NH4Cl (> 98.7 % pure) (0 and 684 mg/kg bw) for a period of 70 days (Arnold et al., 1997). After 70 days, the animals were subjected to diets free of the test chemical for up to 7 days before sacrifice. No compound dependent effects on food consumption, body weights, gross and histopathology of the bladder were observed. NH4Cl in the diet caused a reduction of urine pH and an increase in calcium excretion. This is ascribed to direct inhibition of tubular reabsorption of calcium and increased dissociation of plasma protein-bound calcium due to the decrease in plasma pH, so that more ionised calcium is filtered through the glomerulus. However, although in humans evidence exists that calcium mobilisation from bone is quantitatively important in metabolic acidosis of less than several weeks of duration, it has been argued on the basis of theoretical predictions, that mobilisation of calcium in large amounts cannot be sustained for very long periods, because all of the bone in the body would be dissolved within a few years and such losses could obviously not persist. Although the NOAEL is thus formally below 684 mg/kgbw/day, this value is considered to be irrelevant for human risk assessment.

In a repeated dose study, ammonium bicarbonate (NaHCO3, CAS# 1066 -33 -7) was applied to male albino Wistar rats in the diet (Oliver and Bourke, 1975). One group of animals (8 animals) completed the following treatment: NaHCO3 (2 mmol daily for 6 days), water (6 days), HCl (4 mmol daily for 6 days), HCl (6 mmol daily for 5 days), NaHCO3 (2 mmol daily for 5 days), NaHCO3 (4 mmol daily for 4 days), NaHCO3 (6 mmol daily for 4 days), water (4 days), NH4Cl (4 mmol daily for 5 days). An interval of 3 days was observed between treatments except where the change was only one of dosage. Group 2 consisted of eleven rats. Three rats served as controls throughout. Of the remainder, half received NH4Cl (6 mmol) for 8 days, followed by NH4HCO3 (6 mmol) for a further 8 days. The converse rotation was used in the four other rats. Urine samples for 24 h were collected in HCl and stored at -20°C. The following parameters were analyzed: urea, ammonia, blood pH and blood bicarbonate, total nitrogen in the food. All rats lived to the end of the studies and maintained constant weight throughout experiments with minimal weekly variation (3% +/-0.1). Administration of NaHCO3 (6 mmol or 2.37 g/kg bw/d for 8 days) led to an increase in urinary ammonia to a very small extent and to a marked and statistically significant increase in urea as compared to the control group. Despite the limited information content, the study has been assigned a reliability rating of 2 in an OECD assessment (SIDS Initial Assessment Report for SIAM 22, CAS# 1066 -33 -7, 2006). Although ammonium bicarbonate administration is too short and controlled parameters are limited, this study provides reliable information on the absence of toxicity by repeated administration at the selected dose. No adverse effects were noted, and thus a NOAEL of 474 mg/kg bw/d can be anticipated.

Justification for classification or non-classification

Based on the 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.