Propanoic acid, 2-hydroxy-, ammonium salt (1:1), (2S)-

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient for assessment

Data source

Reference

Reference 1

Reference Type:

review article or handbook

Title:

Toxicological Profile for Ammonia

Author:

ATSDR, Agency for Toxic Substances and Disease Registry

Year:

2004

Bibliographic source:

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Reference 2

Reference Type:

publication

Title:

Prenatal Exposure of Rats to Ammonia Impairs NMDA Receptor Function and Affords Delayed Protection Against Ammonia Toxicity and Glutamate Neurotoxicity

Author:

Minana M.D., Marcaida G., Grisolia S. and Felipo V.

Year:

1995

Bibliographic source:

Journal of Neuropathology and Experimental Neurology, Vol. 54, No. 5, pp. 644-650

Materials and methods

Test material

Test material information

Test animals

Species:

rat

Strain:

Wistar

Administration / exposure

Route of administration:

oral: feed

Duration of treatment / exposure:

from gestational day 1 through lactation day 21

Frequency of treatment:

daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

20 other: % (w/w)

Doses / concentrations 2

Dose / conc.:

4 293 mg/kg bw/day

Examinations

Fetal examinations:

body weight, aspartate aminotransferase activity, NMDA receptor function

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Maternal developmental toxicity

Number of abortions:

not specified

Pre- and post-implantation loss:

not specified

Total litter losses by resorption:

not specified

Early or late resorptions:

not specified

Dead fetuses:

not specified

Changes in pregnancy duration:

not specified

Changes in number of pregnant:

not specified

Other effects:

not specified

Results (fetuses)

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

Rats exposed to ammonium in utero and during lactation, which then received a normal diet, had a statistically significant reduction in body weight gain by 25 and 16% in male and female offspring, respectively, at 120 days of age.
Rats that were continued on the same ammonia diet as their dams had an even greater decrease in body weight
gain (27 and 26% for males and females, respectively) at 120 days of age.

Reduction in number of live offspring:

not specified

Changes in sex ratio:

not specified

Changes in litter size and weights:

not specified

Changes in postnatal survival:

not specified

External malformations:

not specified

Skeletal malformations:

not specified

Visceral malformations:

not specified

Other effects:

effects observed, treatment-related

Description (incidence and severity):

Decreased NMDA receptor function in neurons. Binding of [H3]MK-801 (an NMDA receptor antagonist) to NMDA receptors was reduced by approximately 60% in cerebellar cell cultures from 8-day-old rats exposed to
ammonium in utero and during lactation (dams received 4,293 mg ammonium/kg/day in the diet from gestational day 1 through lactation day 8).
Additionally, aspartate aminotransferase induction was absent in treated neurons (occurred in neurons from control rats), which also indicates impairment of NMDA receptors. Treated neurons were much more resistant to the toxic effects of glutamate than control neurons; since glutamate toxicity is mediated by NMDA receptors, attenuation of glutamate toxicity is indicative of impaired NMDA receptor function.

Effect levels (fetuses)

Key result

Dose descriptor:

LOAEL

Effect level:

4 293 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

fetal/pup body weight changes

Remarks on result:

other: secondary to maternal toxicity

Applicant's summary and conclusion

Conclusions:

In conclusion, in a developmental toxicity, female Wistar rats were exposed to ammonium via the diet at concentrations of 20% (w/w) (corresponding to 4293 mg/kg bw/day) from gestational day 1 through lactation day 21. A reduction in body weight gain by 25 and 16% in male and female offspring, respectively, was observed at 120 days of age. Since only one concentration was tested, the LOAEL was considered to be 20% (w/w) ammonium (corresponding to 4293 mg/kg bw/day).

Executive summary:

In a developmental toxicity study, ammonium was administered to Wistar rats in the diet at dose levels of 20% (w/w) (corresponding to 4293 mg/kg bw/day) from gestational day 1 through lactation day 21.

No information was available concerning maternal effects. Therefore, a maternal NOAEL/LOAEL could not be derived.

Rats exposed to ammonium in utero and during lactation, which then received a normal diet, had a statistically significant reduction in body weight gain by 25 and 16% in male and female offspring, respectively, at 120 days of age. Rats that were continued on the same ammonia diet as their dams had an even greater decrease in body weight gain (27 and 26% for males and females, respectively) at 120 days of age. In addition, decreased NMDA receptor function in neurons was observed in cerebellar cell cultures from 8-day old rats exposed to ammonium in utero and during lactation. Furthermore, aspartate aminotransferase induction was absent in treated neurons, which also indicates impairment of NMDA receptors.

Since only one concentration was tested, the developmental LOAEL is 20% (w/w) in the diet, corresponding to 4293 mg/kg bw/day. In addition, in the statement of EFSA on " Health risk of ammonium released from water fillers [EFSA Journal 2012, 10(10): 2918] it was stated: "Following this treatment, the offspring showed a significant decrease in body weight at 120 days of age. ATSDR (2004) concluded that the effects observed in the offspring were secondary to maternal toxicity."