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Key value for chemical safety assessment

Effects on fertility

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No study data on the toxicity on reproduction by ammonium carbamate are available. As extensively described in the statement in chapter 5.1.3, ammonium carbamate decomposes into ammonium and carbonate at physiological concentrations and pH. This is supported by literature data and hydrolysis studies performed by the registrant. Based on this dissociation process, the study is scientifically unjustified in accordance with section 1 of REACH Annex XI. Both ammonium and carbonate ions are integral components in normal metabolic processes and hence play an essential role in the physiology of man and animals. The dissociation products are not expected to pose any reproduction toxicity risk.

Short description of key information:
In accordance with section 1 of REACH Annex XI, the study is scientifically unjustified, as ammonium carbamate is not expected to represent any reproduction toxicity risk, since it would dissociate in aqueous solutions at physiological pH to yield ammonium ions (NH4+) a and carbonate ions (CO32-) (Wilson et al., 1968). These ions are all integral components in normal metabolic processes and hence play an essential role in the physiology of man and animals.

Effects on developmental toxicity

Additional information

At physiological pH and concentration, ammonium carbamate will dissociate to NH4+ and carbonate ions (see statement in chapter 5.1.3), which represent the potential toxic entities of ammonium carbamate. Due to the lack of data on developmental toxicity, studies with sodium bicarbonate (CAS# 144-55-8), ammonium chloride (CAS # 12125 -02 -9) and ammonium perchlorate (CAS # 7709 -98 -9) were included for the assessment.

25 Female Wistar rats per dose were treated daily with an aqueous solution containing 3.4, 15.8, 73.3 and 340 mg/kg bw/day sodium bicarbonate by gavage through days 6-15 of gestation (US Food and Drug Administration (FDA), 1974). At the end of study period, the foetuses were examined for the presence of external congenital abnormalities, detailed visceral abnormalities and for skeletal defects. The examinations showed that sodium bicarbonate did not affect implantation or the survival of dams and fetuses. The number of abnormalities seen in either soft or skeletal tissues of the test group did not differ from the number occurring spontaneously in the sham-treated controls. The number of abnormalities was increased in animals treated with the positive control (acetylsalicylic acid 250 mg/kg bw). Therefore the NOAEL for developmental toxicity was 340 mg/kg bw/day. Similar negative results for sodium bicarbonate were reported by studies with mice and rabbits for daily doses from 5.8-580 mg/kg bw/day and 3.3-330 mg/kg bw/day, respectively (US Food and Drug Administration (FDA), 1974).

In a developmental toxicity study, ammonium chloride (no data on purity) was administered to pregnant female Sprague Dawley rats (10/dose) in drinking water at 0 and 8.9 mg/kg bw/day through days 7-10 of gestation (Goldman and Yakovac, 1964). The positive control substance sodiumsalicylate (500 mg/kg bw/day) caused increased anomalous foetuses.

Regarding the results with ammonium chloride, acidosis was exhibited by the dams. No malformations were observed in the foetuses. There was an increased incidence of early resorptions and pups growth retardation; however, these effects were considered a consequence of maternal acidosis by the authors. They argued that "The amount of 2.5 mEq/24 hours ammonium chloride consumed by the pregnant rats in the study is sufficient to cause metabolic acidosis in rats weighing between 250 and 300 g. "It should be noted that acidosis observed upon treatment with NH4Cl is likely to be related to the acidic pH of the substance in aqueous media due to its hydrolysis. Ammonium chloride is a salt of a weak base (ammonia) and a strong acid (HCl), thus its hydrolysis will lead to increased concentration of protons, lowering the pH. As hydrolysis of ammonium carbamate will lead to the formation of a weak base (ammonia) and a weak acid (CO2, or carbonic acid), it is not expected that acidosis is relevant for ammonium carbamate. Furthermore, taking into account that ammonium ions (NH4+) and carbonate ions(CO32-) are all integral components in normal metabolic processes and hence play an essential role in the physiology of man and animals, developmental toxicity is not expected for ammonium carbamate.

Ammonium perchlorate was tested in a developmental toxicity study in rabbits. The substance was adminstered to the does via the drinking water from gestational days (GD) 6 to 28 (23 days). On GD 29, the rabbits were sacrificed and the fetuses were examined for developmental alterations. As the thyroid was the expected target organ of the perchlorate ion, blood was collected from does to determine the levels of TSH, T3 and T4, and the thyroid was subjected to histopathologic examination.

The maternal thyroid was the target organ for ammonium perchlorate in this study, which was not surprising in light of the fact that the primary effect of the perchlorate ion is its ability to competitively inhibit uptake of iodide by the thyroid gland, as described by the authors of the study. Increased incidence of thyroid follicular hypertrophy was observed in does treated with 10 mg/kg/day and above, and significantly decreased T4 was observed in does treated with 30 mg/kg/day and above. However, these observations were clearly described by the authors as effects caused by the perchlorate ion based on its mode of action and are not attributable to the ammonium ion.

No maternal deaths related to treatment were observed. Ammonium perchlorate exposure to as high as 100 mg/kg/day did not affect the caesarean sectioning or litter parameters studied. All values were within the historical control ranges.

Based on these data, the maternal no-observable-adverse-effect level (NOAEL) for ammonium perchlorate was 1.0 mg/kg-day. The developmental NOAEL for ammonium perchlorate was found to be 100.0 mg/kg-day for rabbits. In conclusion, ammonium perchlorate was not a developmental toxicant in pregnant rats in this study, and the effects on the maternal thyroid are most likely attributable to exposure to the perchlorate ion and not the ammonium ion.

Justification for classification or non-classification

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

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