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The results of an acute oral study according to OECD 401 was assessed as a key study. Here, a LD50 in the range of >681-< 1470 mg/kg bw was determined. No data are available for acute inhalation toxicity of ammonium carbamate. In a read across approach, data from ammonia and sodium bicarbonate assessing acute inhalation toxicity indicated an estimated LC50 of 6.6 mg/L/4 h (rats) and > 4.74 mg/L/4 h (rats), respectively. The LD50 assessed in an acute dermal toxicity study according to OECD 402 (key study) was > 5000 mg/kg bw in rats. This result is supported by the outcome of an older study (OECD 434) for ammonium sulfate, where a LD50 of >2000 mg/kg was determined.

Key value for chemical safety assessment

Additional information

Oral

In the key study (comparable to OECD guideline 401), groups of Wistar rats (5 rats/sex/dose) were given single oral doses of ammonium carbamate (analytical purity >99.8%) in Carboxymethyl Cellulose (CMC) by gavage at doses of 215, 681, 1470 mg/kg bw and observed for 14 days. 2/10 Animals died within 24 hours at the mid dose group and all animals in the high dose group perished within 24 hours. An LD 50 between 681 – 1470 mg/kg bw was calculated. Clinical signs of toxicity included poor general state, apathy, scrubby fur, staggering and dyspnoea. No pathological findings were noted at necropsy (BASF AG 1989).

 

Supporting these findings are the results of another acute oral study performed in the rat (male and female). An LD 50 of 1380 mg/kg bw was calculated after gavage administration of ammonium carbamate (technical) (no data on purity) in water at doses of 50, 100, 200, 400, 800, 1000, 2000, 4000 mg/kg bw to several groups of 1 to 5 rats. Deaths occurred within 30 min of exposure. Clinical signs of toxicity included apathy, convulsions and accelerated respiration (BASF AG 1956).

Inhalation

There are no data on inhalation toxicity testing with ammonium carbamate. Since in aqueous solution ammonium carbamate decomposes via the corresponding carbonate and bicarbonate releasing ammonia and CO2, assessment of this endpoint is performed using a weight of evidence approach using data from sodium bicarbonate (CAS# 144-55 -8) and ammonia (CAS# 7664-41-7).

In a limit test, five male and five females Sprague-Dawley rats were exposed (whole body) to dust aerosol particles of sodium bicarbonate at a concentration of 4.74 ± 1.03 mg/L sodium bicarbonate (analytical purity >99.5%) for 4.5 h (Product Safety Labs, 1992). Particle analysis revealed a mass median aerodynamic diameter of 2.9 ± 1.77 µm and 2.7 ± 2.04 µm, measured in two samplings of two minutes duration, respectively. While ocular and/or nasal discharge in 6/10 rats was observed within one day after exposure, no mortality was noted. Therefore, the LC50 was found to be > 4.74 mg/L/4.5 hr.

Regarding ammonia, a study with rats and a study with mice are available. In the study with rats, male Wistar rats were exposed to concentrations of 9870, 10230, 11300, 12500 and 13240 mg/m3 ammonia for 1h. The LC50 for ammonia was estimated at ca. 11590 mg/m3 air (Appelman et al., 1982). Using the modified Haber's law (Cn x t = constant, where C is concentration and n = 1 for extrapolation from shorter to longer exposure durations), this results in LC50 of 2898 mg/m3/4 h. Assuming that the maximum quantity of NH3 possibly released from ammonium carbamate would be 43.6%, an LC50 of ca. 6646 mg/m3 air (6.6 mg/L/4h) can be estimated for a 4 hour exposure duration for ammonium carbamate.

In the study with mice (Kapegnian et al., 1982), male ICR mice were exposed for 1 hour to 2408, 2954 and 3402 mg/m3 gaseous ammonia(corresponding to 3440, 4220 and 4860 ppm). The established LC50 was ca. 2960 mg/m3/1 h. Using the modified Haber's law (see above), a LC50 of 740 mg/m3/4h for ammonia can be calculated. Assuming that the maximum quantity of ammonia possibly released from ammonium carbamate would be 43.6%, this results in LC50 of 1697 mg/m3/4h (1.7 mg/L/4 h) for ammonium carbamate.

The study of Appelman et al., 1982 is considered to be superior to the study of Kapeghian et al., 1982 for assessing the acute inhalation toxicity of ammonia for the following reasons:

- the study is performed according to a protocol equivalent or similar to OECD Guideline 403;

- the study has been performed on rats, which are the preferred species according to the OECD Guideline 403;

- detailed presentation of materials, methods and results is reported in the study;

- analytical verification of the test atmosphere has been performed.

Based on these considerations, the value from the study with rats, i.e. LC50 of 6.6 mg/L/4 hr shall be taken forward for risk assessment.

Dermal

Ammonium carbamate was tested in a dermal acute toxicity study conducted according to GLP and OECD guideline 402.

The test substance, ammonium carbamate, was administered once dermally for a 24-hour period under semi-occlusive dressing to Crl:CD(SD) albino rats for the determination of a median lethal dosage (LD50). The test substance was administered to 1 group of 5 male and 5 female rats at a dose level of 5000 mg/kg (5.0 g/kg). Mortality, clinical observations, dermal findings (Draize, 1965; Appendix C), and body weight changes were evaluated over a 14-day observation period. All animals were subjected to a gross necropsy. There were no deaths, remarkable body weight changes, or clinical findings. Dermal findings noted during the study consisted of very slight to severe erythema, very slight to moderate edema, eschar, pinpoint scabbing, necrosis, scabbing within dose site, exfoliation, and desquamation. Scabbing at the application site was noted for 1 male and 2 females at the scheduled necropsy.

Based on the results of this study, the LD50 of ammonium carbamate was greater than 5000 mg/kg when administered once for 24 hours to the clipped, unabraded skin of male and female albino rats.

Studies with another ammonium compound, ammonium sulfate (CAS# 7783-20-0), were evaluated in a weigh-of-evidence approach. No mortality was observed within 14 days in 5-6 weeks old Wistar rats (3/sex) receiving an application of 2000 mg/kg bw ammonium sulfate under open conditions (Yamanaka, 1990). The LD50 was thus >2000 mg/kg bw.

Justification for classification or non-classification

Based on the LD50 from the available oral studies in rats, ammonium carbamate is "of moderate toxicity after single ingestion". The R-phrase R22 is warranted according to EU Directive 67/548/EEC. According to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008, the substance should be classified as Category 4, H302 (Harmful if swallowed).

Concerning acute dermal toxicity and acute inhalation toxicity, based on the results of available studies with rats on structural analogues of ammonium carbamate, ammonium sulfate and ammonia, respectively, no classification is required according to EU Directive 67/548/EEC and the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.