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Diss Factsheets

Administrative data

Description of key information

Anhydrous ammonia is a gas hence testing for acute toxicity via the oral route is technically unfeasible. The substance is corrosive and is classified accordingly: waivers are therefore proposed in respect of acute oral and dermal toxicity. A number of non-standard acute inhalation toxicity studies in the rat and mouse indicate that the substance is toxic by inhalation. A key LC50 value of 9850 mg/m³ in rats exposed for 60 minutes was retained.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Published study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
no guideline followed
Principles of method if other than guideline:
Assessment of acute inhalation toxicity in the rat following various exposure periods
GLP compliance:
not specified
Remarks:
: published study
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
Groups of male and female SPF-bred Wistar rats (Cpb:WU, Wistar Random), obtained from the Central Institute for the Breeding of Laboratory Animals, TNO, Zeist. The average age of the rats on arrival was 7-8 weeks, and the body weights of males and females varied between 150-170 g, and 130-140 g, respectively. After exposure rats were housed 5 per cage for the 14 day observation period. Food (standard laboratory rat diet) and tap water were available during the observation period, but were witheld during exposure. The temperature and relative humidity of the room were maintained at 21±1°C and 50-60%, respectively.
Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
Groups of male and female rats were exposed to dynamic atmospheres containing different concentrations of ammonia for 10, 20, 40 or 60 mins. The atmosphere was an ammonia/air mixture, introduced at a rate of 25 L/min.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
by titration
Duration of exposure:
10 - 60 min
Concentrations:
Various exposure concentrations were used to establish the LC50 value for ammonia at 10, 20, 40 or 60 mins. Actual range of concentrations used not noted.
No. of animals per sex per dose:
5 males and 5 females per group
Control animals:
no
Details on study design:
Groups of female and male rats were exposed to dynamic atmospheres containing different concentrations of ammonia for 10, 20, 40 or 60 mins. The aim of the study was to establish the relationship between exposure concentration and exposure period and mortality. Following exposure rats observed for clinical signs for 14 days. Body weight was recorded at days 1, 2, 4, 7, and 14. Clinical symptoms were recorded, and autopsy was performed after the 14 day observation period.
Statistics:
Probit method used to calculate LC50 values
Preliminary study:
A preliminary study was not reported
Sex:
male/female
Dose descriptor:
LC50
Effect level:
28 130 mg/m³ air
95% CL:
26 040 - 30 380
Exp. duration:
10 min
Sex:
male/female
Dose descriptor:
LC50
Effect level:
19 960 mg/m³ air
95% CL:
19 050 - 20 920
Exp. duration:
20 min
Sex:
male/female
Dose descriptor:
LC50
Effect level:
14 170 mg/m³ air
95% CL:
13 500 - 14 870
Exp. duration:
40 min
Sex:
male/female
Dose descriptor:
LC50
Effect level:
11 590 mg/m³ air
95% CL:
10 860 - 12 380
Exp. duration:
60 min
Sex:
male
Dose descriptor:
LC50
Effect level:
9 850 mg/m³ air
95% CL:
8 490 - 11 430
Exp. duration:
60 min
Sex:
female
Dose descriptor:
LC50
Effect level:
13 770 mg/m³ air
95% CL:
12 350 - 15 340
Exp. duration:
60 min
Mortality:
Mortality data are presented in Table 1.
Clinical signs:
other: Eye-irritation; especially in animals exposed for 60 minutes, wet noses, nasal discharge, mouth breathing, restlessness and laboured respiration were seen during exposure.
Body weight:
Not reported
Gross pathology:
Macroscopic examination revealed haemorrhagic lungs in animals that died during the study and also those that were sacrificed at study termination.
Other findings:
No other findings

Table 1. Mortality Data

Ammonia Concentration (mg/m³ air)

Exposure time (min)

Mortality rate (%)

Males

Females

Both Sexes Combined

20950

10

0

0

0

23380

20

0

10

26410

100

20

60

27220

100

0

50

37820

100

80

90

18290

20

60

0

30

19030

20

0

10

19450

100

40

70

21420

60

60

60

23200

100

80

90

12620

40

40

0

20

13410

80

20

50

15870

80

20

50

16290

100

60

80

16840

100

40

70

9870

60

40

20

30

10230

80

0

40

11300

100

0

50

12500

100

20

60

13240

100

40

70

Interpretation of results:
harmful
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
As the exposure period increased, the LC50 decreased in value from 28130 mg
Executive summary:

The acute inhalation toxicity of ammonia was assessed by exposing groups of male and female Wistar rats were to atmospheric ammonia for 10, 20, 40 or 60 minutes. Following exposure surviving rats were housed 5 per cage and observed for 14 days.

Clinical symptoms included eye irritation, wet noses and nasal discharge. Autopsy revealed haemorrhagic lungs. The 60 minute LC50 in male rats was 9850 mg/m³ air. The 60 minute LC50 in female rats was 13770 mg/m³ air.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
9 850 mg/m³ air
Quality of whole database:
Three published literature reports are available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Acute oral toxicity


Anhydrous ammonia is a gas, hence testing the substance for acute oral toxicity is neither relevant nor technically feasible. Furthermore, anhydrous ammonia gas and its aqueous solutions are corrosive. A waiver is proposed on the basis that the substance is a gas and is corrosive.


 


According to Part 3 of Annex VI of the CLP Regulation 1272/2008/EC, anhydrous ammonia, has a harmonised classification for corrosive effects. It is classified for corrosivity as: Category 1B, H314 “Causes severe skin burns and eye damage” according to Annex VI of the CLP Regulation 1272/2008/EC. The specific rules for adaptation from Column 1 of the standard information requirements in Column 2 state that acute toxicity testing is not required for substances which are classified as corrosive to the skin (Annex VII, No. 8.5). Testing for acute toxicity is not required and is considered to be unjustified both scientifically and on animal welfare grounds.


 


Acute dermal toxicity


No data are available. A waiver is proposed as the substance is classified as corrosive. Dermal exposure to anhydrous ammonia will be dominated by local effects at the site of contact and significant systemic toxicity is unlikely.


 


According to Part 3 of Annex VI of the CLP Regulation 1272/2008/EC, anhydrous ammonia, has a harmonised classification for corrosive effects. It is classified for corrosivity as: Category 1B, H314 “Causes severe skin burns and eye damage” according to Annex VI of the CLP Regulation 1272/2008/EC. The specific rules for adaptation from column 1 of the standard information requirements in column 2 state that acute toxicity testing is not required for substances which are classified as corrosive to the skin (Annex VIII, No. 8.5). Testing for acute toxicity is not required and is considered to be unjustified both scientifically and on animal welfare grounds.


 


Acute inhalation toxicity


The acute inhalation toxicity of the substance has been investigated in a number of studies in rats and mice, using non-standard short exposure periods. Further testing is not proposed as the substance is corrosive.


 


The acute inhalation toxicity of ammonia was assessed in a key study by exposing groups of male and female Wistar rats by whole body exposure to atmospheric ammonia for 10, 20, 40 or 60 minutes. Following exposure surviving rats were housed 5 per cage and observed for 14 days.


Clinical symptoms included eye irritation, wet noses and nasal discharge. Autopsy revealed haemorrhagic lungs. The 60 minute LC50 in male rats was 9850 mg/m³ air. The 60 minute LC50 in female rats was 13770 mg/m³ air (Appelman et al.,1982).


Based on the 9850 mg/m3 value in males, corresponding to 13140 ppm, the 4h corrected LC50 (CLP rule: divide by 2) is  6570 ppm (Cat4)  and the 4h LC50  (ATE) corrected (Haber rule: divide by 4) is 3285 ppm (Cat 4).


 


The acute inhalation toxicity of ammonia gas was assessed in male albino mice by whole body exposure as supporting study. 100% mortality occurred at the highest concentration of 4860 ppm. At higher concentration, mortality usually occurred within 30 minutes of exposure initiation. The lungs of mice that died during exposure were congested with evidence of haemorrhage. The lungs of animals from every treatment group sacrificed displayed a mild to moderate degree of chronic focal pneumonitis histologically. The liver and heart weights were increased in animals that died during exposure to 4860 ppm.


 


The 1 hour LC50 of ammonia gas to male mice is 4230 ppm (Kapeghian et al.,1982).


 


The acute inhalation toxicity of ammonia gas to rats was determined during single exposure times of 5, 15, 30 or 60 minutes as supportive study. Ammonia concentrations ranged from 6000 to 100 mg/m³. Ammonia poisoning in high concentrations (6000, 3000, 1000 mg/m³) was characterised by dyspnoea, irritation of the respiratory passages and eyes and cyanosis of the limbs. The animals were highly excitable and convulsed; the convulsions caused death. The LC50 during exposures of 5 and 15 minutes were 18693 mg/m³ and 12160 mg/m³, respectively, while for 30 and 60 minute exposures the values were 7035 mg/m³ and 7939 mg/m³ (Prokop'eva et al.,1973).


 


In a final supportive study, 20 white rats were placed in a special chamber and exposed to ammonia vapours for up to 3 hours. Air samples were taken from the chamber every 10 min for 2 h (Gubeeva, 2012). At the end of the exposure the larynx was examined using a stereoscope. Histological examination of internal organs was also carried out. The blood serum pH was determined using Lach-Ner universal indicator paper. Histological examination was also conducted on the internal organs of control animals.


 


Experimental modelling of inhalation poisoning with ammonia was carried out in a specialized chamber with a volume of 2.3, which had a hermetically closing loading and unloading hatch, and an exhaust ventilation system for creating a negative pressure inside the chamber, equipped with a manometer. Inside the chamber there was an ammonia evaporator (SAG-1) and a fan for movement of the vapours. To produce the ammonia vapours, the active substance in the form of 25% aqueous solution was introduced into the evaporator and was heated to 60°C. The concentration of the ammonia vapours was determined with a UG-2 universal gas analyser. Air samples were taken from the chamber every 10 min for 2 h.


All the test animals died within 3 hours. The histological examination of different internal organs laid emphasis on the lungs and upper respiratory tract. Changes in blood pH values were measured. It is shown that the severity of inhalation intoxication with ammonia vapours depends on the development of asphyxia as a result of laryngeal oedema and spasm. Ammonia vapours penetrating into the bloodstream cause alkalinization of the blood.

Justification for classification or non-classification

Based on the oral toxicity data in the Dossier of anhydrous ammonia, most conservative acute toxicity classification is Acute tox 3 H331 (Toxic if inhaled).