Ammonium acetate

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Test method was not according to any guideline. No GLP.

Objective of study:

absorption

distribution

excretion

metabolism

Principles of method if other than guideline:

The uptake and urea formation of ammonia in the liver were studied in healthy volunteers by means of hepatic vein catheterization after an oral administration of Ammonium acetate.

GLP compliance:

no

Radiolabelling:

yes

Species:

human

Strain:

other: not applicable

Sex:

not specified

Details on test animals or test system and environmental conditions:

Test subjects had been on the nitrogen-poor diet (2.7 g of N) for 4 days prior to the experiment. They were in the post absorptive state.

Route of administration:

oral: feed

Vehicle:

not specified

Duration and frequency of treatment / exposure:

One single administration

Remarks:

Doses / Concentrations:
10.5-11.1 mg of ammonia nitrogen (0.80 meq) per minute.

No. of animals per sex per dose / concentration:

Two subjects (no data on sex distribution).

Control animals:

no

Details on dosing and sampling:

- Two or three basal periods were studied before starting the infusion.
- The estimated splanchnic blood flow (ESBF) was calculated by means of Cardio-Green throughout the experiments.
- Blood samples for determination of urea and ammonia were taken from a peripheral artery and from the hepatic vein at the beginning and at the end of periods of about 5-20 min, for about 2 hr.
- The production (output) and the consumption (uptake), respectively, of the liver were calculated by multiplying concentration differences between hepatic vein blood and peripheral arterial blood by ESBF.
- Heparinized blood samples for ammonia determinations were always examined immediately after withdrawing and rapid centrifuging.
- Ammonia, alfa-amino nitrogen, total protein, and urea nitrogen concentrations were determined in the plasma, as were the 24-hr excretion of ammonia, alfa-amino nitrogen, urea nitrogen, creatinine, and total nitrogen in the urine.

Details on absorption:

N absorption after oral loading of NH4+ is complete.

Details on distribution in tissues:

Human oral exposure data for NH4+ clearly indicate that it readily enters the portal circulation and is delivered to the liver.

Details on excretion:

Urea, the main metabolite, was excreted in the urine. Output of urea from the liver corresponded to the amount of NH4+ ingested. Excretion data for humans orally exposed to ammonia have been quantified with respect to excretion of isotope from 15N-labeled ammonium salts, thus providing an indication of the turnover rate of the compound within the body and excretion route of its metabolites.

Metabolites identified:

yes

Details on metabolites:

In nitrogen-deficient persons, NH4+ (as ammonium acetate) administered orally was absorbed and carried directly to the liver where most of it was converted to urea.

Ammonium salt administered orally to humans led to a corresponding increase in blood urea concentration transported out of the liver, leading the authors to conclude that orally ingested ammonium salt is quickly and almost completely converted in the liver and eliminated from the body as urinary urea.

Conclusions:

Interpretation of results: other: orally ingested ammonium salt is quickly and almost completely converted in the liver and eliminated from the body as urinary urea.
Ammonium salt administered orally to humans led to a corresponding increase in blood urea concentration transported out of the liver, leading the authors to conclude that orally ingested ammonium salt is quickly and almost completely converted in the liver and eliminated from the body as urinary urea.

Executive summary:

The uptake and urea formation of ammonia in the liver were studied in healthy volunteers by means of hepatic vein catheterization after an oral administration of Ammonium acetate.

N absorption after oral loading of NH4+ is complete.

Human oral exposure data for NH4+ clearly indicate that it readily enters the portal circulation and is delivered to the liver.

Urea, the main metabolite, was excreted in the urine. Output of urea from the liver corresponded to the amount of NH4+ ingested. Excretion data for humans orally exposed to ammonia have been quantified with respect to excretion of isotope from 15N-labeled ammonium salts, thus providing an indication of the turnover rate of the compound within the body and excretion route of its metabolites.

Ammonium salt administered orally to humans led to a corresponding increase in blood urea concentration transported out of the liver, leading the authors to conclude that orally ingested ammonium salt is quickly and almost completely converted in the liver and eliminated from the body as urinary urea.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Test method was not according to any guideline. No GLP.

Objective of study:

distribution

metabolism

Principles of method if other than guideline:

The uptake and urea formation of ammonia in the liver were studied in healthy volunteers by means of hepatic vein catheterization after an intravenous administration of Ammonium acetate.

GLP compliance:

no

Radiolabelling:

no

Species:

human

Strain:

other: not applicable

Sex:

not specified

Details on test animals or test system and environmental conditions:

Test subjects had been on the nitrogen-poor diet (2.7 g of N) for 4 days prior to the experiment. They were in the postabsorptive state.

Route of administration:

intravenous

Vehicle:

not specified

Duration and frequency of treatment / exposure:

One single administration

Remarks:

Doses / Concentrations:
10.5-11.1 mg of ammonia nitrogen (0.80 meq) per minute.

No. of animals per sex per dose / concentration:

Two subjects (no data on sex distribution)

Control animals:

no

Details on dosing and sampling:

- Two or three basal periods were studied before starting the infusion.
- The estimated splanchnic blood flow (ESBF) was calculated by means of Cardio-Green throughout the experiments.
- Blood samples for determination of urea and ammonia were taken from a peripheral artery and from the hepatic vein at the beginning and at the end of periods of about 5-20 min, for about 2 hr.
- The production (output) and the consumption (uptake), respectively, of the liver were calculated by multiplying concentration differences between hepatic vein blood and peripheral arterial blood by ESBF.
- Heparinized blood samples for ammonia determinations were always examined immediately after withdrawing and rapid centrifuging.
- Ammonia, alfa-amino nitrogen, total protein, and urea nitrogen concentrations were determined in the plasma, as were the 24-hr excretion of ammonia, alfa-amino nitrogen, urea nitrogen, creatinine, and total nitrogen in the urine.

Details on distribution in tissues:

The nitrogen from NH4+, which gains entry into the general circulation, is distributed to cells throughout the body and incorporated into tissues.

Metabolites identified:

yes

Details on metabolites:

Intravenous administration of NH4+ (as ammonium salts) to people with a nitrogen deficiency (in negative nitrogen balance) resulted in no increase in urinary urea.
Ammonium ion is metabolized to urea and glutamine mainly in the liver. The nitrogen is released from glutamine within tissue cells and used for protein synthesis as needed.

The nitrogen from NH4+, which gains entry into the general circulation, is distributed to cells throughout the body and incorporated into tissues.

Intravenous administration of NH4+ (as ammonium salts) to people with a nitrogen deficiency (in negative nitrogen balance) resulted in no increase in urinary urea. Ammonium ion is metabolized to urea and glutamine mainly in the liver. The nitrogen is released from glutamine within tissue cells and used for protein synthesis as needed.

Conclusions:

Interpretation of results: other: After an intravenous administration, Ammonium ion is metabolized to urea and glutamine mainly in the liver.
The nitrogen from NH4+, which gains entry into the general circulation, is distributed to cells throughout the body and incorporated into tissues.
Intravenous administration of NH4+ (as ammonium salts) to people with a nitrogen deficiency (in negative nitrogen balance) resulted in no increase in urinary urea. Ammonium ion is metabolized to urea and glutamine mainly in the liver. The nitrogen is released from glutamine within tissue cells and used for protein synthesis as needed.

Executive summary:

The uptake and urea formation of ammonia in the liver were studied in healthy volunteers by means of hepatic vein catheterization after an intravenous administration of Ammonium acetate.

The nitrogen from NH4+, which gains entry into the general circulation, is distributed to cells throughout the body and incorporated into tissues.

Intravenous administration of NH4+ (as ammonium salts) to people with a nitrogen deficiency (in negative nitrogen balance) resulted in no increase in urinary urea. Ammonium ion is metabolized to urea and glutamine mainly in the liver. The nitrogen is released from glutamine within tissue cells and used for protein synthesis as needed.

Reference 3

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Test method was not according to any guideline. No GLP.

Objective of study:

excretion

Principles of method if other than guideline:

The intravenous administration of Ammonium acetate to dogs results in measurable levels of free ammonia in expired air. Simultaneous measurement of the physiologic dead space permits the calculation of the partial pressure of ammonia in alveolar air.
Seven mongrel dogs were studied. Following anesthesia, 100 meq of NaHCO3 was administered to each dog intravenously to elevate blood pH and increase the fraction of total ammonium present as NH3. The air expired by the dog was bubbled through 10 mL of 0.1 N HCl for 20 minutes to serve as a control. After the control period, 0.2 M Ammonium acetate was infused intravenously at a constant rate for periods of time ranging from 46 to 90 minutes. During the administration of Ammonium acetate the air expired by the dog was permitted to bubble through a fresh solution of HCl; this converted any free NH3 in the expired air to NH4Cl. Midway during the experimental period, measurements of arterial CO2 tension, expired air CO2 tension, and the volume of expired air were made by standard methods.
The concentrations of ammonium present in the control and experimental samples were determined by nesslerization. The volume of the respiratory dead space was calculated by means of the Bohr equation.
In two dogs simultaneous measurements of arterial pH and total blood ammonium concentrations were made. By applying the Henderson-Hasselbalch equation, it was possible to estimate the theoretical partial pressure of ammonia in arterial blood. In four dogs the completeness of extraction of ammonia by the HCl solution was tested by means of rebubbling expired air through a second aliquot of HCl.

GLP compliance:

no

Radiolabelling:

no

Species:

dog

Strain:

other: mongrels

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: ca. 15 kg

Route of administration:

intravenous

Vehicle:

not specified

Details on exposure:

Ammonium acetate was infused intravenously at a constant rate for periods of time ranging from 46 to 90 minutes.

Duration and frequency of treatment / exposure:

One single administration.

Remarks:

Doses / Concentrations:
0.2 M

No. of animals per sex per dose / concentration:

7 dogs were used (no data on sex distribution)

Control animals:

yes

Positive control reference chemical:

No data

Details on dosing and sampling:

During the administration of Ammonium acetate the air expired by the dog was permitted to bubble through a fresh solution of HCl; this converted any free NH3 in the expired air to NH4Cl. Midway during the experimental period, measurements of arterial CO2 tension, expired air CO2 tension, and the volume of expired air were made by standard methods.
The concentrations of ammonium present in the control and experimental samples were determined by nesslerization. The volume of the respiratory dead space was calculated by means of the Bohr equation.
In two dogs simultaneous measurements of arterial pH and total blood ammonium concentrations were made. By applying the Henderson-Hasselbalch equation, it was possible to estimate the theoretical partial pressure of ammonia in arterial blood. In four dogs the completeness of extraction of ammonia by the HCl solution was tested by means of rebubbling expired air through a second aliquot of HCl.

Details on excretion:

During control periods no measurable amount of NH3 was found in expired air.
In each dog, Ammonium acetate administration produced measurable quantities of NH3 in expired air. The quantity of NH3 in air was small, averaging 3.8 E-07 mL/mL of air.
The average partial pressure of NH3 for the seven dogs was 7 E-04 mm Hg.

Metabolites identified:

not measured

In each dog, Ammonium acetate administration produced measurable quantities of NH3 in expired air. The quantity of NH3 in air was small, averaging 3.8 E-07 mL/mL of air. The average partial pressure of NH3 for the seven dogs was 7 E-04 mm Hg.

Conclusions:

Interpretation of results: other: Ammonium acetate administration produced measurable quantities of NH3 in expired air.
In each dog, Ammonium acetate administration produced measurable quantities of NH3 in expired air. The quantity of NH3 in air was small, averaging 3.8 E-07 mL/mL of air.
The average partial pressure of NH3 for the seven dogs was 7 E-04 mm Hg.

Executive summary:

The intravenous administration of Ammonium acetate to dogs results in measurable levels of free ammonia in expired air. Simultaneous measurement of the physiologic dead space permits the calculation of the partial pressure of ammonia in alveolar air.

Seven mongrel dogs were studied. Following anesthesia, 100 meq of NaHCO3 was administered to each dog intravenously to elevate blood pH and increase the fraction of total ammonium present as NH3. The air expired by the dog was bubbled through 10 mL of 0.1 N HCl for 20 minutes to serve as a control. After the control period, 0.2 M Ammonium acetate was infused intravenously at a constant rate for periods of time ranging from 46 to 90 minutes. During the administration of Ammonium acetate the air expired by the dog was permitted to bubble through a fresh solution of HCl; this converted any free NH3 in the expired air to NH4Cl. Midway during the experimental period, measurements of arterial CO2 tension, expired air CO2 tension, and the volume of expired air were made by standard methods.

The concentrations of ammonium present in the control and experimental samples were determined by nesslerization. The volume of the respiratory dead space was calculated by means of the Bohr equation.

In two dogs simultaneous measurements of arterialpHand total blood ammonium concentrations were made. By applying the Henderson-Hasselbalch equation, it was possible to estimate the theoretical partial pressure of ammonia in arterial blood. In four dogs the completeness of extraction of ammonia by the HCl solution was tested by means of rebubbling expired air through a second aliquot of HCl.

During control periods no measurable amount of NH3 was found in expired air. In each dog, Ammonium acetate administration produced measurable quantities of NH3 in expired air. The quantity of NH3 in air was small, averaging 3.8 E-07 mL/mL of air. The average partial pressure of NH3 for the seven dogs was 7 E-04 mm Hg.

Description of key information

Short description of key information on bioaccumulation potential result:

Basic toxicokinetics: Weight of evidence: The distribution, as well as the metabolic fate of ammonia, depends on the route of administration. After intestinal absorption, ammonium ions are primarily transformed by the liver to urea, and subsequently excreted in the urine. In contrast, intravenously-administered ammonium salts are more available as non-essential nitrogen for protein synthesis.

On the other hand, Ammonium acetate administration produced measurable quantities of NH3 in expired air.

Additional information

Weight of evidence: Experimental data on Ammonium Acetate:

In the first publication, it is explained that the distribution, as well as the metabolic fate of ammonia, depends on the route of administration. After intestinal absorption, ammonium ions are primarily transformed by the liver to urea, and subsequently excreted in the urine. In contrast, intravenously-administered ammonium salts are more available as non-essential nitrogen for protein synthesis.

In the second publication, the intravenous administration of Ammonium acetate to dogs resulted in measurable levels of free ammonia in expired air. Simultaneous measurement of the physiologic dead space permited the calculation of the partial pressure of ammonia in alveolar air. During control periods no measurable amount of NH3 was found in expired air. In each dog, Ammonium acetate administration produced measurable quantities of NH3 in expired air. The quantity of NH3 in air was small, averaging 3.8 E-07 mL/mL of air. The average partial pressure of NH3 for the seven dogs was 7 E-04 mm Hg.

In the experimental study, Boyano et all. (endpoint Repeated dose toxicity: oral 07.05.01_11) shows that dieta with very high acetate ammonium level do not produce significant differences between experimental and control animals were observed at the other times studied till 90 days of study (blood ammonia analysis demonstrated only a significative difference between high ammonia diet and control animals at 7th day). The result of the study shows that ammonia is metabolised extensively, whay confirms that the substance is no toxic at high teste doses as well as unlikely can reach foetus in vivo and produce effects (as showed in the thestudy of Miñana et all, endpoint developmental toxicity / teratogenicity 07.08.302_15).