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Key value for chemical safety assessment

Effects on fertility

Description of key information
No additional studies are available.
Effect on fertility: via oral route
Dose descriptor:
NOAEL
408 mg/kg bw/day
Additional information

Screening study

No evidence of any effects on fertility or foetal development were seen at dose levels up to 1500 mg/kg bw/d with the read-across compound diammonium phosphate (HLS, 2002); this dose level is equivalent to approximately 408 mg/kg bw/day ammonia.

Two-generation study

A guideline-comparable two-generation study with ammonium perchlorate did not identify any effects on reproductive parameters at dose levels of up to and including 100 mg/kg bw/day. The study did identify effects on the parental thyroid associated with perchlorate exposure, however findings are not attributable to ammonium. The results of the study therefore confirm that exposure to ammonium is not associated with reproductive toxicity (York et al, 2001).

Conclusion

There is no evidence that exposure to ammonium ions will cause reproductive toxicity. Inhalation exposure to ammonia will result in an equilibrium in the blood (at physiologically relevant pH) between non-ionised ammonia (NH3) and ionised ammonium (NH4+) in a ratio of approximately 1:100. The same equilibrium will exist in animals orally exposed to ammonium salts, therefore read-across is appropriate. Human maternal blood contains measurable levels of ammonia as a consequence of protein catabolism; the blood in the hepatic portal circulation contains much higher levels of ammonia due to its generation from urea by the gastrointestinal flora. Ammonia is rapidly and effectively detoxified in the liver by the urea cycle and also via additional pathways, therefore will not accumulate and is unlikely to cause any reproductive effects.


Short description of key information:
No evidence of any reproductive effects was seen in studies with ammonium salts. The physiological role of ammonia indicates that it is unlikely to be a reproductive toxin at relevant exposure levels.

Effects on developmental toxicity

Description of key information
No evidence of any developmental effects was seen in studies with ammonia or ammonium salts.  The physiological role of ammonia indicates that it is unlikely to be a developmental toxin at relevant exposure levels.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
100 mg/kg bw/day
Effect on developmental toxicity: via inhalation route
Dose descriptor:
NOAEC
25 mg/m³
Additional information

No evidence of developmental toxicity was seen in a guideline-compliant rabbit study with ammonium perchlorate (York et al, 2001) at the highest dose level of 100 mg/kg bw/day.

The influence of ammonium ions on foetal development was investigated in mice in a non-standard study involving in vitro exposure prior to transplantation into dams (Lane & Gardner, 1994). Examination on gestational day 15 showed an apparent relationship between the duration of exposure and the incidence of exencephaly. Embryos that were cultured with various concentrations of ammonium ion before being transferred to recipient dams showed increased incidence of exencephaly and a decreased percentage of implantation sites with increased ammonium concentration. It is unclear how embryos might be exposed to ammonia or ammonium in vivo or if in vivo exposure would affect foetal development and implantation in a way similar to that described in this study.

No evidence of foetal toxicity was seen in a study in pigs (Diekman et al, 1993) exposed to maternally toxic concentrations of ammonia by inhalation. Although the design of the study is somewhat limited, it can be concluded that the relatively low concentrations of ammonia required to induce local irritant effects are very unlikely to cause systemic toxicity or any developmental toxicity.

Conclusion

There is no evidence that exposure to ammonium ions causes specific developmental toxicity in vivo. Inhalation exposure to ammonia will result in an equilibrium in the blood (at physiologically relevant pH) between non-ionised ammonia (NH3) and ionised ammonium (NH4+) in a ratio of approximately 1:100. The same equilibrium will exist in animals orally exposed to ammonium salts, therefore read-across is appropriate. Human maternal blood contains measurable levels of ammonia as a consequence of protein catabolism; levels of ammonia in foetal blood are slightly higher. The blood in the hepatic portal circulation contains much higher levels of ammonia due to its generation from urea by the gastrointestinal flora. Ammonia is rapidly and effectively detoxified in the liver by the urea cycle and also via additional pathways, therefore will not accumulate and is unlikely to cause any developmental toxic effects at relevant exposure levels.

Justification for classification or non-classification

The available data do not indicate that ammonia is a reproductive or developmental toxin: no classification is proposed.

Additional information