Ammonium chloride (NH4Cl), a lysosomotropic substance that increases intralysosomal pH, lowers the reovirus output when it infects mouse L cells[2].

In vivo myocardial cell survival is enhanced by ammonium chloride (0.28 M in drinking water), which reduces inflammation, apoptosis, contractile dysfunction, cardiac hypertrophy, and autophagy[1].

Animal/Disease Models: 8-9weeks old C57B/L6 mice[1]
Doses: 0.28 M in drinking water (5 mg/kg doxorubicin once a week for 2 weeks)
Route of Administration: 0.28 M in drinking water (5 mg/kg doxorubicin once a week for 2 weeks)
Experimental Results: Effectively improved doxorubicin (DOX)-induced cardiomyocyte apoptosis and cardiac dysfunction in mice.

Absorption, Distribution and Excretion
Completely absorbed within 3–6 h. In healthy persons, absorption of ammonium chloride given by mouth was practically complete. Only 1 to 3% of the dose was recovered in the feces.
Excretion: Urine
Data not found.
Data not found.
From human incidentally exposures it was learnt that following oral administration, ammonium chloride is rapidly absorbed from the GI tract, complete absorption occurring within 3 -6 hours. Only 1 -3% of the dose was recovered in the feces. Substantial first pass metabolism occurs in the liver. For animals, after repeated oral administration, ammonium chloride enters readily the body and main targets for its toxicity are kidneys.
Ammonium chloride is effectively absorbed from the gastrointestinal tract ... . In healthy persons, absorption of ammonium chloride given by mouth was practically complete. Only 1 to 3% of the dose was recovered in the feces.
Following oral administration, ammonium chloride is rapidly absorbed from the GI tract, complete absorption occurring within 3-6 hours. However, an oral dosage form of ammonium chloride is no longer commercially available in the US.
Oral administration of ammonium chloride to healthy male and female volunteers at 9 mg/kg bw produced transient increases in blood ammonia in about half of the subjects. Patients with cirrhosis showed a greater and more prolonged increase over a higher baseline. This confirms substantial first pass metabolism in the liver.

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Metabolism / Metabolites
Ammonium ion is converted to urea in the liver; chloride ion replaces bicarbonate.
When ammonium ion is converted to urea, liberated hydrogen ion reacts with bicarbonate and other body buffers ... chloride ion displaces bicarbonate ion; latter is converted to carbon dioxide ... chloride load to kidneys is increased and appreciable amount escapes reabsorption along with equivalent amount of cation ... and isoosmotic quantity of water.
The toxicity of ammonium chloride depends on the ammonia which enters the living organism and hence the cell. This substance is readily absorbed by the gastrointestinal tract, and utilized in the liver to form amino acids and proteins. When ammonium ions are converted to urea, liberated hydrogen ion reacts with bicarbonate ion to form water and carbon dioxide. The chloride ion displaces the bicarbonate ion. Chloride is loaded into the kidneys. The increased chloride concentration in the extracellular fluid produces an increased load to the renal tubules. Increase excretion of electrolytes and water causes loss of extracellular fluid and promotes the mobilization of edema fluid.
/Ammonium chloride/ is metabolized in the liver to form urea and hydrochloric acid.
Male Sprague-Dawley rats gavaged with 1000 umol (15)N ammonium chloride each day for 5 days were found to excrete low, but significant amounts of excess (15)N nitrate in their urines on the five days of treatment and on the five subsequent days. A total of 0.28 + or - 0.03 umol excess (15)N nitrate (mean + or - SE) per rat was recovered which indicates that ammonia is converted to nitrate in a yield of approximately 0.0080%.

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Biological Half-Life
Unknown

Toxicity Summary
IDENTIFICATION AND USE: Ammonium chloride is a white, fine or coarse, crystalline powder. it is a good fertilizer for important crops in rainy climates, particularly for rice. It is not registered for current use in the U.S., but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses. Ammonium chloride is used also as a flux in zinc and tin plating; electroplating, electrolytic refining of zinc; etching solutions in manufacture of printed circuit boards; in dry and Leclanche batteries; manufacturing of explosives; flame suppressant; hardener for formaldehyde-based adhesives; mordant for dyes and printing. It is used as medication particularly in diuretics, expectorants. HUMAN EXPOSURE AND TOXICITY: Potential symptoms of overexposure to fumes are irritation of eyes, skin, and respiratory system; cough, dyspnea, pulmonary sensitization. Large doses of ammonium chloride may cause metabolic acidosis secondary to hyperchloremia, especially in patients with impaired renal function. Other adverse effects of excessive ammonium chloride dosage include rash, headache, hyperventilation, bradycardia, progressive drowsiness, mental confusion, and phases of excitement alternating with coma. Calcium-deficient tetany, hyperglycemia, glycosuria, twitching, hyperreflexia, and EEG abnormalities have also been reported. Most of these adverse effects are secondary to ammonia toxicity resulting from inability of the liver to convert the ammonium ion to urea. Because rapid IV injection may increase the likelihood of ammonia toxicity, IV infusions of ammonium chloride should be administered slowly to permit metabolism of ammonium ions by the liver. Patients receiving ammonium chloride should be closely monitored for signs and symptoms of ammonia toxicity such as pallor, sweating, irregular breathing, vomiting, bradycardia, cardiac arrhythmias, local or generalized twitching, asterixis, tonic seizures, and coma. ANIMAL STUDIES: Acute exposure in mice by intravenous administration resulted in hyperventilation and clonic movements which were followed sometimes by tonic extensor convulsions, but usually by profound coma; death was preceded by convulsions, but survivors made complete and rapid recovery. This syndrome was potentiated by short periods of hypoxia. In rabbits, replacement of aq. humor with 1% solution of ammonium chloride has caused considerable hyperemia of iris, but by next day eyes were almost normal, and in another day were completely recovered. The ingestion of ammonium chloride in doses of around 500-1000 mg/kg bw/day, for periods ranging from 1 to 8 days, has induced metabolic acidosis in mice, guinea-pigs, rats, rabbits, and dog. Pulmonary edema, central nervous system dysfunction, and renal changes are reported to have occurred after ingestion of ammonium chloride. Ammonium chloride is reported to cause alterations in calcium and bone metabolism in various species. Specific toxic effects on the kidneys as renal hypertrophy were found in rats receiving ammonium chloride in the diet. Other salts (ammonium citrate or sodium chloride) did not induce such effects. Rabbits showed cellular swelling and karyolysis of kidney tubulus cells after two daily oral administrations of 16.2 g/animal ammonium chloride. One-sixth molar ammonium chloride was given to mice orally in the drinking water after day 7 during pregnancy and although the offspring were small sized no congenital defects were found. In other study mice were given 600 mg/kg orally at 8 and 10 am and 12 and 1 pm on day 10 of gestation and produced 7% ectrodactyly in the offspring. Negative in the Ames test using Salmonella typhimurium TA 98, TA 100, TA 1535, TA 1537, TA 1538 at doses with and without metabolic activation. Negative in the Ames test using Escherichia coli WP2uvrA with and without metabolic activation. ECOTOXICITY STUDIES: Four simultaneous early life-stage ammonia tests with small mouth bass were carried out at 4 different pH levels ranging from 6.6 to 8.7. Exposure to ammonium chloride solutions began on 2 to 3-day old embryos and lasted for 32 days. Concentrations found to retard growth ranged from 0.056 mg/L at pH 6.60 to 0.865 mg/L at pH 8.68. Groups of 180 Coho salmon were exposed to ammonium chloride at concentrations of 0.019-0.33 mg/L for 91 days. In high dose animals the hemoglobin content and hematocrit was significantly reduced and the percentage of immature erythrocytes in blood was increased. The key species, the earthworm Eisenia fetida, was subjected to a series of tests in solid phase mesocosms and full-scale units. The solid phase tests showed a relatively low toxicity to ammonium with ammonium chloride having an LC50 for ammonium of 1.49 g/kg.

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Protein Binding
Data not found.

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Interactions
Cisplatin (cis-diamminedichloroplatinum II, CDDP) acts as a therapeutic agent by initiating cellular apoptosis. However, side-effects and drug resistance limit the clinical use of cisplatin. Numerous studies have focused on the drug-target interactions, cellular pharmacology and pharmacokinetics of cisplatin. Newly developed treatment strategies are needed in order to be used in combination with cisplatin, with the aim to minimize toxicity and to circumvent cisplatin resistance. Ammonium chloride (NH4Cl) is widely used in various areas, but its use as a combination agent with cisplatin for the treatment of cancer cells has not been previously reported. In the present study, we showed that NH4Cl could be potentially used as an effective agent in cisplatin combination treatment of HeLa human cervical cancer (HCC) cells. Cisplatin was found to inhibit cell growth, as well as to induce cell apoptosis and DNA double-strand breaks. In addition, treatment with NH4Cl increased the rate of cell apoptosis and the activation of caspase-3. Particularly, we found that NH4Cl treatment increased cisplatin induced phosphorylation of H2AX. In conclusion, our data indicate that NH4Cl enhances cisplatin cytotoxicity through increased DNA damage in HeLa HCC cells.
Large doses of ammonium chloride acidify the urine, thus decr the ionization of chlorpropamide (Diabinese) and decr its urinary excretion.
Ammonium chloride tends to render the urine acidic, thereby incr the possibility of aminosalicylic acid crystalluria.
It is proposed that the inhibition of aldosterone by spironolactone may impair the ability of the kidney to secrete hydrogen ions, and in the presence of acidifying doses of ammonium chloride the combination may produce systemic acidosis.
For more Interactions (Complete) data for AMMONIUM CHLORIDE (16 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral 1650 mg/kg
LD50 Rat im 30 mg/kg
LD50 Rat iv 7-10 mmol/kg
LD50 Mouse oral 1300 mg/kg bw
For more Non-Human Toxicity Values (Complete) data for AMMONIUM CHLORIDE (8 total), please visit the HSDB record page.

[1]. NH4Cl treatment prevents doxorubicin-induced myocardial dysfunction in vivo. Life Sci. 2019;227:94-100.

[2]. Canning WM, Fields BN. Ammonium chloride prevents lytic growth of reovirus and helps to establish persistent infection in mouse L cells. Science. 1983;219(4587):987-988.

[3]. Lysosome dysfunction enhances oxidative stress-induced apoptosis through ubiquitinated protein accumulation in Hela cells. Anat Rec (Hoboken). 2013 Jan;296(1):31-9.

Ammonium chloride is a white crystalline solid. It is soluble in water(37%). The primary hazard is the threat posed to the environment. Immediate steps should be taken to limit its spread to the environment. It is used to make other ammonium compounds, as a soldering flux, as a fertilizer, and for many other uses.
Ammonium chloride is an inorganic chloride having ammonium as the counterion. It has a role as a ferroptosis inhibitor. It is an inorganic chloride and an ammonium salt.
Ammonium chloride is an inorganic compound with the formula NH4Cl. It is highly soluble in water producing mildly acidic solutions.
Ammonium Chloride is a systemic and urinary acidifying salt. Ammonium chloride helps maintain pH and exerts a mild diuretic effect. This acid forming salt also exerts an expectorant effect by irritating the mucous membranes and is used for alleviation of cough.
An acidifying agent that has expectorant and diuretic effects. Also used in etching and batteries and as a flux in electroplating.
See also: Ammonium Chloride; Caramiphen Edisylate (component of); Ammonium chloride; potassium iodide (component of); Ammonium chloride; chlorine dioxide (component of) ... View More ...

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Drug Indication
1. Expectorant in cough syrups. 2. The ammonium ion (NH4+) in the body plays an important role in the maintenance of acid-base balance. The kidney uses ammonium (NH4+) in place of sodium (Na+) to combine with fixed anions in maintaining acid-base balance, especially as a homeostatic compensatory mechanism in metabolic acidosis. The therapeutic effects of Ammonium Chloride depend upon the ability of the kidney to utilize ammonia in the excretion of an excess of fixed anions and the conversion of ammonia to urea by the liver, thereby liberating hydrogen (H+) and chloride (Cl–) ions into the extracellular fluid. Ammonium Chloride Injection, USP, after dilution in isotonic sodium chloride injection, may be indicated in the treatment of patients with: (1) hypochloremic states and (2) metabolic alkalosis.

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Mechanism of Action
Ammonium chloride increases acidity by increasing the amount of hydrogen ion concentrations. Ammonium chloride can be used as an expectorant due to its irritative action on the bronchial mucosa. This effect causes the production of respiratory tract fluid which in order facilitates the effective cough.
The acid-forming properties of ammonium chloride result from dissociation of the salt to an ammonium cation and a chloride anion. In patients with normal hepatic function, the ammonium cation is converted to urea by the liver and a hydrogen cation is released which reacts with a bicarbonate ion to form water and carbon dioxide. The chloride anion combines with fixed bases in the extracellular fluid, thereby reducing the alkaline reserve of the body. The net result is the displacement of bicarbonate ions by chloride anions. The displacement of bicarbonate by chloride alters the bicarbonate:carbonic acid ratio if the body and acidosis results. The increased chloride concentration in the extracellular fluid produces an increased load to the renal tubules and appreciable amounts of chloride anions escape reabsorption. These anions are excreted along with cations and water. Sodium is the principal cation excreted; however, potassium excretion may also be increased to some degree. By increasing the excretion of both extracellular electrolytes and water, ammonium chloride causes a net loss of extracellular fluid and promotes the mobilization of edema fluid.

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Therapeutic Uses
Mesh Heading: diuretics, expectorants
Ammonium chloride is used as a systemic acidifier in patients with metabolic alkalosis resulting from chloride loss following vomiting, gastric suction, gastric fistula drainage, and pyloric stenosis. Ammonium chloride also has been used in the treatment of diuretic-induced chloride depletion. A solution containing isotonic or hypotonic sodium chloride with potassium chloride usually has been more effective than ammonium chloride in hypokalemic patients. Ammonium chloride also has been used to treat alkalosis resulting from excessive use of alkalinizing drugs.
Ammonium chloride has been used in a variety of conditions to induce incipient acidosis for the purpose of promoting diuresis, particularly in edematous conditions associated with hypochloremia. Ammonium chloride had limited value as a diuretic when used alone because of its limited period of effectiveness, but the drug has been useful when administered alone or in combination with a xanthine diuretic (e.g., caffeine, pamabrom) for short-term therapy to relieve temporary water-weight gain, edema, bloating, and/or full feeling associated with premenstrual and menstrual periods. Ammonium chloride also has been used for its diuretic effect in Meniere's syndrome.
MEDICATION (VET): As urinary acidifier, and to increase its rate of flow when it is given in large doses. Reduces incidence of urinary calculi in cattle and sheep. Increases intestinal tract acidity, thus increases calcium absorption and this is utilized in preventing milk fever in cattle. Stimulant and liquefier of bronchial secretions.
For more Therapeutic Uses (Complete) data for AMMONIUM CHLORIDE (11 total), please visit the HSDB record page.

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Drug Warnings
Ammonium salts are contra-indicated in patients with hepatic or renal impairment.
Patients receiving ammonium chloride should be closely monitored for signs and symptoms of ammonia toxicity such as pallor, sweating, irregular breathing, vomiting, bradycardia, cardiac arrhythmias, local or generalized twitching, asterixis, tonic seizures, and coma.
Sustained correction of hypochloremia cannot be achieved by administering ammonium chloride alone in patients with secondary metabolic alkalosis resulting from intracellular potassium depletion; concomitant administration of potassium chloride is necessary in such patients.
Ammonium chloride should be administered with caution to patients with pulmonary insufficiency or cardiac edema. The drug should not be used in patients with primary respiratory acidosis and high total carbon dioxide and buffer base.
For more Drug Warnings (Complete) data for AMMONIUM CHLORIDE (12 total), please visit the HSDB record page.

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Pharmacodynamics
Systemic acidifier. In liver ammonium chloride is converted into urea with the liberation of hydrogen ions ( which lowers the pH) and chloride.

CLH4N

53.49

53.003

12125-02-9

Ammonium chloride-15N;39466-62-1

25517

White to off-white solid powder

1.52

100 °C750 mm Hg

340 °C (subl.)(lit.)

1 mm Hg ( 160.4 °C)

1.642

1.178

1

1

0

2

0

0

NLXLAEXVIDQMFP-UHFFFAOYSA-N

InChI=1S/ClH.H3N/h1H;1H3

azanium;chloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : 100 mg/mL (1869.51 mM)
DMSO : 50 mg/mL (934.75 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (46.74 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (46.74 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (46.74 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)