Ammonium sulphate

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Limited documentation

Objective of study:

distribution

Principles of method if other than guideline:

no data

GLP compliance:

not specified

Radiolabelling:

no

Species:

rabbit

Strain:

other: Japanese white

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
Japanese white rabbits
- Weight at study initiation: 3.4 - 3.8 kg
no further data

ENVIRONMENTAL CONDITIONS: no data

Route of administration:

other: gastric tube

Vehicle:

physiological saline

Duration and frequency of treatment / exposure:

single dose

Dose / conc.:

1 500 other: mg/kg/bw

No. of animals per sex per dose / concentration:

3 (test group);
2 (control group)

Control animals:

yes, concurrent vehicle

Positive control reference chemical:

no

General findings

The three rabbits used in this experiment showed similar symptoms. Mydriasis and slight irregular respiratory rhythms appeared at 10 to 20 min after ingestion of the ammonium sulfate solution. Local convulsions persisting for 5 to 10 min in the face or in the extremities starting 15 to 25 min after ingestion and soon after it spread to every part of the body, at which time they exhibited opisthotonus lasting for 1 0 to 20 s which repeated itself several times.

After the general convulsions, heart rates decreased suddenly (N=1) or gradually (N=2) depending on the rabbit and the pneumonic respiration became quiet and weak. In 60 to 70 min after the ingestion, all the rabbits fell into breathlessness along with cardiac arrest.

Blood examination

Blood gas analysis:

The value of pH, HCO3 and Base Excess decreased promptly. On the other hand, PO2 and PCO2 did not show remarkable changes during the experiment until the animals died. These results show that severe metabolic acidosis developed after ingestion of the test substance.

Ammonium and sulfate ion concentration:

The concentration of ammonium in serum had already increased remarkably 5 min after ingestion (1095 +/- 535 µg/dl , mean +/- SD), until it reached 11000 +/- 1200 µg/dl after 60 min

Inorganic sulfate ion concentration started to increase at 10 min after ingestion and its level continued to increase linearly to 20 +/- 4.9 mEq/l after 60 min

Biochemical analysis:

Electrolytes of Na+, K+, Cl - and Ca2 + did not show any significant change during the experiment except for a moderate increase in K+ just before cardiac arrest. Concentration of released enzymes such as AST, ALT and LDH remained constant and normal levels were maintained throughout the experiment. Also, the values of BUN and creatinine were always within a normal range.

Histological observation

Brain, heart, lung, spleen, kidney, liver and stomach were observed microscopically, but no pathological changes such as hemorrhage, degeneration or necrosis of tissue were found.

In control group of rabbit ingesting saline, there was no significant finding on physiological monitoring, blood examination, histological observation.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

no data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Limited documentation.

Objective of study:

other: clearance

Qualifier:

no guideline available

GLP compliance:

not specified

Radiolabelling:

yes

Remarks:

35S

Species:

other: hamster, guinea pig, rabbit

Route of administration:

inhalation: aerosol

Duration and frequency of treatment / exposure:

5 minutes

Remarks:

Doses / Concentrations:
1 to 3 mg/m³

No. of animals per sex per dose / concentration:

8-12 per group

It was demonstrated that the particles with a size of 0.3 and 0.6 µm (MMAD) reached the lung; however, a substantial proportion of the test substance was found in the nose and gastrointestinal tract. Total respiratory tract deposition was greater with the larger particle size in all studies. The clearance from the lung (via the blood and urinary tract) was determined to be T1/2 = 18 -20 minutes and rate of lung clearance was similar for the two particle sizes and for all species.

The T1/2 for blood was determined as follows:

• hamster: 3 hours
• guinea pig: 1 -3 hours
• rabbit: > 6 hours

Hamsters showed a large gastrointestinal deposition whereas for the rabbits and guinea pigs, the maximum was reached as early as 1 hour after exposure. By 6 hours after exposure, 96% of the total collectable sulfate was present in the urine. The results of the clearance experiments performed in this study suggested that there was no specific difference. Apart from the hamsters, the recovery of 35S in the urine was incomplete.

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Reference 3

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Study period:

no data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Reliable review.

GLP compliance:

not specified

Human and animal data on toxicokinetic parameters of ammonia are summarized.

1. Uptake and absorption

At low concentrations, inhaled ammonia dissolves in the mucous fluid lining the upper respiratory tract and little reaches the lower airways. Initial retention is about 80% in both the dog and man, but, in man, it falls to less than 30% in less than 27 min. In rats, increases in blood-ammonia were measured following short-term exposure to ammonia at 220 mg/m³ but not at 23 mg/m³. The increases were less marked with longer exposure. Calculated blood-ammonia increases with exposure to air containing 18 mg/m³ are about 10% of fasting levels.

Ammonia is formed in the human intestinal tract by the biological degradation of nitrogenous matter, including secreted urea, in quantities of about 4 g/day. Nearly all of this is absorbed (mainly passively) and is metabolized in the liver on first passage, so that only small amounts reach the systemic circulation.

2. Distribution

Ammonia is normally present in all tissues constituting a metabolic pool. Its distribution is pH dependent, since NH3 diffuses more easily than NH4+. Oral administration of ammonium chloride to healthy male and female volunteers at 9 mg/kg body weight 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.

Administration of 15N-labelled ammonium compounds to experimental animals indicated that the initial distribution of 15N depended on the route of administration and that, after parenteral administration, more was distributed to organs other than the liver.

3. Metabolic transformation

Ammonia is taken up by glutamic acid in many tissues, and this will take part in a variety of transamination and other reactions,

the nitrogen being incorporated in non-essential amino acids. In the liver, ammonia is used in the synthesis of protein by the Krebs-Henseleit cycle.

4. Excretion and turnover

The principal means of ammonia excretion varies between phyla. Mammals excrete urea and secrete ammonium in the kidney tubules as a means of hydrogen ion excretion. Faecal and respiratory excretion are insignificant. Exhaled air may contain volatilized ammonia from the microfloral degradation of salivary urea. In man, on a 70 g protein/day diet, 70% of administered ammonium 15N is lost in a week; on a 20 g protein/ day diet, 35% is lost.

Additional information

In aqueous environments, such as the body the ammonium sulfate is completely dissociated into the ammonium (NH4 +) and the sulfate (SO4 2-) ions. At physiological pH in aqueous media, the ammonium ion is in equilibrium with un-ionized ammonia, according to the following equation: NH4+ + H2O <--> NH3 + H3O+ .

The ammonium ion serves a major role in the maintenance of the acid-base balance. In the normal pH range of blood, the NH4+/NH3 ratio is about 100 (WHO, 1986).

An ammonium ion via the equilibrium with ammonia is readily taken up. Some evidence exists also for an active transport of the ammonium ion from the intestinal tract. It was shown that ammonia transport by the human colon still occurred when the luminal pH was reduced to 5, where nonionized ammonia would be virtually absent (WHO, 1986).

Absorbed ammonium is transported to the liver and metabolized to urea and excreted via the kidneys. Minor amounts of nitrogen are incorporated in the physiological N-pool (WHO, 1986).

Absorption of sulfate depends on the amount ingested. 30 - 44% of sulfate was excreted in the 24-h urine after oral administration of magnesium or sodium sulfate (5.4 g sulfate) in volunteers. At high sulfate doses that exceed intestinal absorption, sulfate is excreted in feces. Intestinal sulfate may bind water into the lumen and cause diarrhoea in high doses. Sulfate is a normal constituent of human blood and does not accumulate in tissues. Sulfate levels are regulated by the kidney through a reabsorption mechanism. Sulfate is usually eliminated by renal excretion. It has also an important role in the detoxification of various endogenous and exogenous compounds, as it may combine with these to form soluble sulfate esters that are excreted in the urine (EPA, 2002).

Studies in Animals

In vivo Studies

In rabbit, hamster and guinea pig studies it was demonstrated that S35-labelled ammonium sulfate aerosols with a size of 0.3 and 0.6 µm (MMAD) reached the lung, however a substantial proportion of the compound was found in the nose. The clearance from the lung (via the blood and urinary tract) was determined to be 18 to 20 minutes. From the collectable sulfate in the urinary tract 95 % was excreted within 6 hours. The results of clearance studies suggested that there was no species difference. The induction of aryl hydrocarbon hydroxylase (an enzyme that acts in the metabolism of benzo(a)pyrene and other carcinogens) in the lung is not inhibited by ammonium sulfate (there are reports of other air pollutants to cause this effect) (EPA, 1978).

There are no studies with human subjects or in vitro studies with human tissue available with ammonium sulfate.

Conclusion

In aqueous media, ammonium sulfate dissociates in the ammonium and sulfate ions (NH4 +, SO4 2-). These can be taken up into the body by the oral and respiratory routes. Absorbed ammonium is transported to the liver and there metabolized to urea and excreted via the kidneys. Ammonium is also an endogenous substance that serves a major role in the maintenance of the acid-base balance. Minor amounts of ammonium nitrogen are incorporated in the physiological N-pool. Sulfate is a normal intermediate in the metabolism of endogenous sulfur compounds, and is excreted unchanged or in conjugated form in urine.