Registration Dossier

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
47.6 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
47.6 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Dose descriptor:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
36 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Dose descriptor starting point:
NOAEC

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.8 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.8 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEL

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Additional information - workers

Overview

The substance is gaseous therefore the relevant route of exposure is by inhalation. Once inhaled, the substance will exist in the body in solution as aqueous ammonia / ammonium hydroxide with an equilibrium between NH4+ and NH3 strongly (>99.9%) in favour of NH4 +. Nevertheless the dossier includes studies performed by other exposure routes with aqueous ammonia and related water-soluble salts of ammonia. Anhydrous ammonia is classified as corrosive and studies using this substance identify local effects at the site of contact. Studies with other related compounds allow the elucidation of systemic toxicity, are therefore relevant and are included in this dossier.

Toxicokinetics

Absorption

Ammonia is generated by the bacterial flora of the gastrointestinal tract (~4 g/day) and as a very small water-soluble molecule, is likely to be rapidly and extensively absorbed. The results of a study in the rat (Schaerdel et al, 1983) indicate that the gaseous substance is absorbed into the bloodstream following inhalation exposure; this is consistent with the water solubility and small molecular size of the substance. Significant dermal absorption is not considered to be likely under exposure scenarios where the integrity of the skin barrier is maintained. If the skin is compromised (e.g. in cases involving burns), dermal absorption may be more extensive.

Distribution

Ammonia is distributed to all tissues in the body and is capable of crossing the blood-brain barrier.

Metabolism

No studies of metabolism are available, however the physiological role of ammonia as a product of normal metabolism (protein catabolism) is very well characterised. Ammonia is rapidly detoxified in the liver by the urea cycle. The urea cycle consists of five enzymes: carbamoylphosphate synthetase I (CPS I), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL) and arginase. The initial reaction of the urea cycle is the formation of carbamoyl phosphate from ammonia and bicarbonate, a reaction catalysed by CPS I, which requires N-acetylglutamate as an allosteric cofactor. Condensation of carbamoyl phosphate with ornithine yields citrulline (by OTC); this in turn condenses with aspartate to give argininosuccinate (by ASS), a reaction that requires the cleavage of two further high-energy phosphate bonds. Argininosuccinate is hydrolysed to fumarate and arginine (by argininosuccinase). Arginine is cleaved by arginase to give urea and ornithine. OTC, like CPS I, is also a major mitochondrial protein; the remaining enzymes are in the cytoplasm of hepatocytes. Urea synthesis cannot therefore be saturated at realistic substrate concentrations. The urea cycle is high capacity and the capacity also increases short-term and long-term in reponse to increased demand (e.g. in response to dietary protein intake). It is estimated that some 7 to 25% of the ammonia delivered via the portal vein escapes periportal urea synthesis and is used for glutamine synthesis

Excretion

Ammonia is rapidly detoxified in mammals by conversion to urea by the urea cycle in liver cells and is subsequently excreted (as urea) in urine following glomerular filtration. Ammonium ions (NH4 +) are also excreted by the kidney. Hepatic excretion of urea (15 -30% of that generated) results in the generation of ammonia by the gastrointestinal flora, and subsequent reabsoprtion.

Physiological production of ammonia and intake from other sources

Ammonia plays a key role in the nitrogen metabolism in all mammalian species. It is a product of both protein and nucleic acid catabolism, and a precursor for non-essential amino acids and other nitrogenous compounds. Approximately 4 g of ammonia are produced daily by intestinal bacteria. For comparison, the amounts of ammonia by daily intake through inhalation, ingestion (food and drink) and cigarette smoking have been estimated to be approximately 18 mg, <1 mg and <1 mg, respectively. Endogenously produced ammonia enters the portal circulation and is rapidly metabolized to urea and glutamine in the liver. Ammonia is primarily excreted as urea and urinary ammonium compounds through the kidney, however exhaled breath contains ammonia concentrations of 0.1 -2.2 mg/m³. These values, which are higher than those expected from equilibrium with ammonia levels in plasma and lung parenchyma, are most likely due to the synthesis of ammonia from salivary urea by oral microflora. Venous plasma levels of ammonia in healthy humans range from about 0.2 -0.9 mg/L in adults and children older than 1 month. In newborns, these intervals are 0.3-2.1 mg/L and 0.45 -1.1 mg/L for premature and mature babies, respectively. Congenital errors of metabolism (related to urea cycle enzymes) or other disease states (severe liver disease, e.g., cirrhosis) result in excess circulating ammonia levels (hyperammonaemia), which are associated with the clinical symptoms of hepatic encephalopathy in adults and decreased food intake, vomiting seizures, and lethargy in neonates and children. Correlating ammonia blood levels are 1.5 mg/L and 1.7 -2.6 mg/L, respectively. Comatose states are usually not present until ammonia levels reach >3 mg/L (Health Council of the Netherlands. Ammonia; Evaluation of the effects on reproduction, recommendation for classification. The Hague: Health Council of the Netherlands, 2009; publication no. 2009/01OSH).

The body excretes approximately 30 g urea/day; urea is synthesised by the hepatic urea cycle from ammonia generated by protein catabolism. Therefore it can be calculated that the body typically produces 16 g/day ammonia, although this figure is influenced by the amount of dietary protein. Therefore it can be concluded that exposure to ammonia at quantities in this range will be without toxicological effect. Ammonia is toxic and therefore exposures greatly exceeding the normal production may overwhelm the normal detoxification mechanisms. The normal serum level of ammonia is 0.15 -100 ug/dL. Assuming a blood volume of 5L (55% serum), this is equivalent to approximately 0.4 -2.75 mg ammonia present in the blood of a normal adult at any point in time. However it is notable that, due to the generation of ammonia by gastrointestinal tract bacteria, the concentration of ammonia in the hepatic portal circulation is much higher than that in the rest of the systemic circulation. Ammonia is also produced by the foetus and ammonia levels in foetal blood are slightly higher than those in the maternal circulation.

Acute toxicity

A waiver is appropriate for acute oral toxicity as the substance is a gas. However data are available (Smyth et al, 1941) which report an oral LD50 value of 350 mg/kg bw in the rat for ammonium hydroxide (aqueous ammonia), which is an aqueous solution of the substance. No data are available for acute toxicity by the dermal route: 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. 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 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 (Appelman et al,1982). The acute inhalation toxicity of ammonia gas was assessed in male albino mice. 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. 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).

Irritation

Anhydrous ammonia is listed on Annex I of Directive 67/548/EEC with classification as (R34) 'Causes burns', therefore waivers are acceptable for skin and eye irritation. Nevertheless, the available data are reported. Prokop'eva et al (1973) report skin burns in rats exposed to anhydrous ammonia. Vernot et al (1977) report corrosive effects for a 20% aqueous solution but not for a 10% aqueous solution. No information is available on eye irritation, however can be assumed that the substance causes severe eye irritation,. Animal data and human reports indicate that the substance is a respiratory irritant.

Sensitisation

No data are available for skin sensitisation: a waiver is proposed. Anhydrous ammonia is listed on Annex I of Directive 67/548/EEC with classification as (R34) 'Causes burns'. Testing for skin sensitisation is not justified on scientific grounds or for reasons of animal welfare. The local dermal effects of the substance will be dominated by irritation/corrosion and sensitisation is considered to be unlikely. It is considered unlikely that ammonia is a respiratory sensitiser. The local respiratory tract effects of the substance will be dominated by irritation. There are no reports of occupational asthma attributable to ammonia exposure. Ammonia is exhaled in small quantities as a consequence of its presence in the blood from protein catabolism.

Repeated dose toxicity

The substance is a gas, therefore the oral route is not a relevant route of exposure. However studies with read-across compounds are available and are evaluated as they provide useful information on the systemic toxicity of ammonia and its salts. A 4 -week screening study in the rat with diammonium phosphate (HLS, 2002) revealed only minor effects on weight gain and clinical chemistry parameters, with a NOAEL of 250 mg/kg bw/d can be determined for this study, equivalent to 68 mg/kg bw/ammonia. A 90 -day study in the rat with ammonium sulphate showed only minor effects at high dose levels (diarrhoea, renal pathology); a NOAEL of 886 mg/kg bw/d was determined, equivalent to 225 mg/kg bw/d ammonia (Tagaki et al, 1999). A NOAEL of 256 mg/kg bw/d (equivalent to 67 mg/kg bw/d) was determined for 1 -year and 2 -year studies by the same group (Ota et al, 2006).

No data are available for repeated dose toxicity by the dermal route. However the substance is classified as corrosive and it can be readily predicted that dermal effects will be dominated by local (site of contact) irritation and corrosion: significant systemic toxicity is not likely.A number of non-standard inhalation studies of various duration and in different species are available. The data indicate that the primary effect of exposure to inhaled anhydrous ammonia is local irritation of the respiratory tract. In a 5-week study in pigs, ammonia concentrations had a highly significant adverse effect upon feed consumption and average daily weight gain. However, there was no significant effect upon efficiency of food conversion. During both trials the high ammonia levels appeared to cause excessive nasal, lacrimal and mouth secretions. This was more pronounced at 100 and 150 ppm than at 50 ppm. Autopsies carried out on three animals showed no significant gross or microscopic differences related to ammonia level. Cultures of Corynebacterium and Pasteurella were obtained from swabs of the ethmoid turbinates from two animals removed from the compartment maintained at 150 ppm and one animal maintained at 100 ppm. There was no evidence of these bacteria in turbinate swabs from other animals (Stombaugh et al, 1969). Sherman and Fischer rats were exposed to environmental ammonia, derived from natural sources for 75 days, or to purified ammonia for 35 days. Rats were either inoculated intranasally with M. pulmonis prior to exposure, or left untreated. The average ammonia concentrations were 105 mg/m3 for 75 days and 175 mg/m³ for 35 days exposure. Ammonia exposure (from either source) significantly increased the severity of the rhinitis, otitis media, tracheitis and pneumonia (including bronchiectasis) characteristic of murine respiratory mycoplasmosis (rats infected with M. pulmonis). The prevalence of pneumonia showed a strong tendency to increase directly with environmental ammonia concentration (Broderson et al,1976). Twenty seven male rats, along with 27 age and weight matched controls, were exposed to atmospheric ammonia gas at a concentration of 350 mg/m³ for up to 8 weeks. The rats were sacrificed after different exposure times. Nasal irritation began on the fourth day. After 3 weeks continuous exposure exposed rats showed nasal irritation and inflammation of the upper respiratory tract. The number of pulmonary alveolar macrophages was similar to that in the controls. After 8 weeks none of the inflammatory lesions were present (Richard et al, 1978). Weatherby (1952) exposed twelve male guinea pigs (plus 6 controls) were exposed to anhydrous ammonia gas for up to 18 weeks (6 hours per day, 5 days per week). The average concentration in air was 119 mg/m³. Four experimental and 2 control animals were sacrificed at 6 week intervals throughout the study. There were no significant findings at necropsy after 6 and 12 weeks exposure. In animals sacrificed after 18 weeks, there was mild congestion of the liver spleen and kidneys, with degenerative changes in the adrenal glands, and hemosiderosis in the spleen indicating hematotoxicity. There was cloudy swelling in the epithelium of the proximal tubules of the kidney as well as albumin precipitation in the lumen with some casts.In a 50-day study (Stolpe & Sedlag, 1976), male Wistar rats were exposed to two concentrations of ammonia gas, continuously for 50 days. Concurrent controls remained untreated. There was no mortality at either concentration (35 or 63 mg/m³), and no treatment-related clinical effects were observed. Body weight gain and food intake, as compared to control values, was not significantly affected by ammonia exposure. At 63 mg/m³ rats showed increased haemoglobin and haematocrit levels compared to controls. The NOAEC for this study was 35 mg/m³.

Genetic toxicity

No evidence of mutagenicity was seen in a guideline-comparable Ames test performed with anhydrous ammonia (Shimizu et al,1985) or in a guideline-compliant Ames test with the read-across substance ammonium sulphate (BASF, 1989). Similarly, there was no evidence of mutagenicity in a non-standard study using E. coli (Szybalski, 1958). No evidence of an increase in the incidence of micronucleated polychromatic erythrocytes was seen in a mouse micronucleus assay performed with the read-across compound ammonium chloride (Hayashi et al, 1988). Ammonia is a simple molecule and does not possess any structural alerts for genotoxicity. Ammonia is present at relatively low levels in the systemic circulation as a consequence of protein catabolism (largely in the liver) and is also present at higher levels in the hepatic portal circulation due to the breakdown of urea by gastrointestinal bacteria. The ubiquitous presence of ammonia in the leads to the conclusion that it is unlikely to be genotoxic. The WHO evaluation (EHC 54, 1986) concludes that there is no evidence that ammonia is mutagenic in mammals. A UK Health Protection Agency (HPA) evaluation similarly concludes that ammonia does not have significant mutagenic potential.

Carcinogenicity

No evidence of carcinogenicity was seen in a rat dietary study with ammonium sulphate (Ota et al, 2006). The NOAEL for this study was 0.6% (dietary level) equivalent to 256 and 284 mg/kg bw/day in males and females respectively [67 and 74 mg/kg bw/d ammonia equivalents]. In a non-standard mechanistic assay, Tsuji et al (1992) exposed MNNG-initiated rats to 0.01% ammonia solution via drinking water. Gastritis was seen in all animals, indicating a local irritant effect. The incidence of gastric tumours was increased in treated animals, suggesting that ammonia may be acting as a promoter of carcinogenesis. Solutions of hydrazine as 0.001%, methylhydrazine as 0.01%, methylhydrazine sulfate as 0.001%, and ammonium hydroxide as 0.3, 0.2 and 0.1% were administered continuously in the drinking water of 5- and 6-week-old randomly bred Swiss mice for their entire lifetime. Similarly ammonium hydroxide as a 0.1% solution was given to 7-week-old inbred C3H mice. Hydrazine and methylhydrazine sulfate significantly increased the incidence of lung tumors in Swiss mice, while methylhydrazine enhanced the development of this neoplasm by shortening its latent period. The ammonium hydroxide treatments in Swiss and C3H mice were, however, without carcinogenic effect, and did not inhibit the development of breast adenocarcinomas in C3H females, which are characteristic of these animals. The present study thus proves for the first time the carcinogenicity of methylhydrazine, provides further evidence of the tumor-inducing capability of hydrazine by itself and negates the possibility that the metabolite of hydrazine, ammonium hydroxide, could interfere in the development of neoplasia (Toth, 1972).

Reproductive toxicity

No evidence of any effects on fertility or foetal development were seen in a screening study at dose levels up to 1500 mg/kg bw/d with the read-across compound diammonium phosphate (HLS, 2002); this dose level is equivalent to approximately 408 mg/kg bw/day ammonia. A guideline-comparable two-generation study with ammonium perchlorate did not identify any effects on reproductive parameters at dose levels of up to and including 100 mg/kg bw/day. The study did identify effects on the parental thyroid associated with perchlorate exposure, however findings are not attributable to ammonium. The results of the study therefore confirm that exposure to ammonium is not associated with reproductive toxicity (York et al, 2001). It is concluded that there is no evidence that exposure to ammonium ions causes reproductive toxicity. Inhalation exposure to ammonia will result in an equilibrium in the blood (at physiologically relevant pH) between non-ionised ammonia (NH3) and ionised ammonium (NH4+) in a ratio of approximately 1:100. The same equilibrium will exist in animals orally exposed to ammonium salts, therefore read-across is appropriate. Human maternal blood contains measurable levels of ammonia as a consequence of protein catabolism; the blood in the hepatic portal circulation contains much higher levels of ammonia due to its generation from urea by the gastrointestinal flora. Ammonia is rapidly and effectively detoxified in the liver by the urea cycle and also via additional pathways, therefore will not accumulate and is unlikely to cause any reproductive effects.

Developmental toxicity

No evidence of developmental toxicity was seen in a guideline-compliant rabbit study with ammonium perchlorate (York et al, 2001) at the highest dose level of 100 mg/kg bw/day. The influence of ammonium ions on foetal development was investigated in mice in a non-standard study involving in vitro exposure prior to transplantation into dams (Lane & Gardner, 1994). Examination on gestational day 15 showed an apparent relationship between the duration of exposure and the incidence of exencephaly. Embryos that were cultured with various concentrations of ammonium ion before being transferred to recipient dams showed increased incidence of exencephaly and a decreased percentage of implantation sites with increased ammonium concentration. It is unclear how embryos might be exposed to ammonia or ammonium in vivo or if in vivo exposure would affect foetal development and implantation in a way similar to that described in this study. No evidence of foetal toxicity was seen in a study in pigs (Diekman et al, 1993) exposed to maternally toxic concentrations of ammonia by inhalation. Although the design of the study is somewhat limited, it can be concluded that the relatively low concentrations of ammonia required to induce local irritant effects are very unlikely to cause systemic toxicity or any developmental toxicity. It is concluded that there is no evidence that exposure to ammonium ions causes specific developmental toxicity in vivo. Inhalation exposure to ammonia will result in an equilibrium in the blood (at physiologically relevant pH) between non-ionised ammonia (NH3) and ionised ammonium (NH4+) in a ratio of approximately 1:100. The same equilibrium will exist in animals orally exposed to ammonium salts, therefore read-across is appropriate. Human maternal blood contains measurable levels of ammonia as a consequence of protein catabolism; levels of ammonia in foetal blood are slightly higher. The blood in the hepatic portal circulation contains much higher levels of ammonia due to its generation from urea by the gastrointestinal flora. Ammonia is rapidly and effectively detoxified in the liver by the urea cycle and also via additional pathways, therefore will not accumulate and is unlikely to cause any devlopmetal toxic effects at relevant exposure levels.

Human data

In a epidemiology study, Xu et al (1998) did not demonstrate any association (odds ratio 1.2) between exposure to ammonia and spontaneous abortion.

The local effects of ammonia on the respiratory tract have been extensively investigated in workers and in human volunteers. Holness et al (1989) investigated the effects of ammonia inhalation of industrial workers and concluded that exposure to ammonia at concentrations of up to 25 ppm is without adverse effect. Ferguson et al (1977) conclude that, after acclimation, continuous exposure of volunteers to 100 ppm, with occasional excursions to 200 ppm, is easily tolerated and has no observed effect on general health. The results of another volunteer study (Keplinger, 1973) indicated irritation at 72 or 134 ppm with more irritation at the higher level. There was some dryness of the nose in one or two subjects exposed to 32 or 50 ppm, but there was not a definite irritation at these levels. In another volunteer study, Silverman et al (1949) demonstrated that exposure to 500 ppm ammonia caused respiratory irritation in volunteers, but did not affect biochemical parameters. Verberk (1977) report that ammonia levels of 140 ppm were not tolerated by non-acclimated volunteers. A literature review by the NRC (1979) reports that immediate irritation is likely at a concentration level of 400 ppm; the severity of the effects increase with exposure concentration with levels of 5000 -10000 ppm possibly fatal.

DNEL derivation

No evidence of marked systemic toxicity has been seen in any study with ammonia or ammonium salts. Data from human patients with genetic defects or liver disease resulting in primary or secondary hyperammonemia, respectively, show that excess levels of ammonia in the blood have the potential to cause serious toxicity including hepatic encephalopathy. In normal individuals, however, blood levels of ammonia are closely regulated through the rapid breakdown of ammonia to urea via the high capacity urea cycle and also by other additional detoxification pathways. Humans are normally exposed to considerable levels of ammonia (estimated to be ~16 g/day) as a consequence of endogenous protein catabolism and also (~4 g/day) as a consequence of the breakdown of urea to ammonia by the gastrointestinal flora. It can therefore be concluded that the human body has the capacity for the rapid and effective detoxification of ammonia. The available data indicate that ammonia do not cause significant systemic toxicity, carcinogenicity, developmental or reproductive toxicity. The substance is classified as corrosive, therefore it is predictable that any effects of exposure will be limited to local effects at the site of contact (skin, respiratory tract). This hypothesis is supported by the results of the human volunteer studies which indicate a threshold for respiratory irritation of 25 ppm, whereas exposure to much (20x) higher levels of ammonia (500 ppm) were without effect on biochemical parameters. It is therefore concluded that protection against the local effects of ammonia will be significantly protective of any potential systemic effects.

Inhalation DNEL:

The critical inhalation effect is local irritation of the respiratory tract

For short-term exposures, ammonia at levels of 50 ppm (36 mg/m³) was tolerated without signs of definite irritation.

However a short-term DNEL of 36 mg/m³ (50 ppm) is proposed, in line with the IOELV (COMMISSION DIRECTIVE 2000/39/EC of 8 June 2000 establishing a first list of indicative occupational exposure limit values in implementation of Council Directive 98/24/EC on the protection of the health and safety of workers from the risks related to chemical agents at work).

A NOAEL of 25 ppm (18 mg/m³) for long-term exposure is derived from the weight of evidence from the human studies.

However a long-term DNEL of 14 mg/m³ (20 ppm) is proposed, in line with the IOELV (COMMISSION DIRECTIVE 2000/39/EC of 8 June 2000 establishing a first list of indicative occupational exposure limit values in implementation of Council Directive 98/24/EC on the protection of the health and safety of workers from the risks related to chemical agents at work).

A DNEL for systemic effect is derived from the 4 -week toxicity and developmental toxicity screening test with diammonium phosphate (DAP). The NOAEL in this study of 250 mg/kg bw/d DAP is equivalent to 68 mg/kg bw/d ammonia. Assuming a bodyweight of 70 kg, this is equivalent to 4.76 g ammonia/day. It is notable that this level of exposure is less than the total amount of ammonia generated in the body (~20 g/day) and is approximately equal to the amount of ammonia produced by intestinal bacteria. Applying the standard assessment factors recommended under REACH would result in the generation of a DNEL value equivalent to a very small proportion (<1%) of the quantity of ammonia normally produced by the body's metabolic processes and is considered to be excessively conservative. For this substance, therefore, an assessment factor of 10 is applied (6.8 mg/kg bw/d, equivalent to 476 mg ammonia/day). The maximum exposure to ammonia therefore represents approximately 10% of the quantities normally generated by the gastrointestinal tract bacteria and is approximately 3% of the total amount of ammonia produced daily by the body.

The oral and inhalation absoprtion of ammonia is likely to be extensive. Dermal absorption is likely to be less extensive. However in the absence of specific information, dermal absorption is considered to be equivalent to oral absorption.

Assuming a breathing rate of 1.25 mg/m³ and an exposure time of 8 hours/day, a short-term inhalation (systemic) DNEL of 47.6 mg/m³ is calculated. Given that this small additional exposure to ammonia is readily detoxified by normal homeostatic mechanisms, the same value of 47.6 mg/m³ is proposed for long-term inhalation (systemic) DNEL.

Dermal DNEL:

The substance is corrosive, therefore dermal exposure should be avoided by the use of PPE and engineering controls. A DNEL for local dermal effects is not quantifiable. A dermal DNEL for systemic effects is derived from the 4-week toxicity and developmental toxicity screening test with DAP, in which a NOAEL of 250 mg/kg bw/d (68 mg/kg bw/d ammonia) was derived. Using the same logic as described above, a non-standard assessment factor of 10 is applied. 10% dermal absorption of ammonia is assumed for non-corrosive concentrations of ammonia (IPCS, 1990), however it is recognised that dermal penetration may be greater (worst case 100%) for higher (potentially corrosive) concentrations of ammonia used by workers. A short-term and long-term systemic dermal DNEL value of 6.8 mg/kg bw/d is therefore derived for workers (who may be exposed to corrosive concentrations), whereas a DNEL value of 68 mg/kg bw/d is appropriate for the general population who will only be exposed to lower (non-corrosive) concentrations. As noted above, the nature of the substance is such that local effects are predicted at exposure levels below those causing systemic effects by this route, and therefore the dermal DNEL for local effects will be protective.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
23.8 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
23.8 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.8 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Overall assessment factor (AF):
5
Dose descriptor:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.2 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Overall assessment factor (AF):
5
Dose descriptor starting point:
NOAEC

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
68 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
68 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEL

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Most sensitive endpoint:
skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.8 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.8 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEL

General Population - Hazard for the eyes

Additional information - General Population

DNEL derivation

No evidence of marked systemic toxicity has been seen in any study with ammonia or ammonium salts. Data from human patients with genetic defects or liver disease resulting in primary or secondary hyperammonemia, respectively, show that excess levels of ammonia in the blood have the potential to cause serious toxicity including hepatic encephalopathy. In normal individuals, however, blood levels of ammonia are closely regulated through the rapid breakdown of ammonia to urea via the high capacity urea cycle and also by other additional detoxification pathways. Humans are normally exposed to considerable levels of ammonia (estimated to be ~16 g/day) as a consequence of endogenous protein catabolism and also (~4 g/day) as a consequence of the breakdown of urea to ammonia by the gastrointestinal flora. It can therefore be concluded that the human body has the capacity for the rapid and effective detoxification of ammonia. The available data indicate that ammonia do not cause significant systemic toxicity, carcinogenicity, developmental or reproductive toxicity. The substance is classified as corrosive, therefore it is predictable that any effects of exposure will be limited to local effects at the site of contact (skin, respiratory tract). This hypothesis is supported by the results of the human volunteer studies which indicate a threshold for respiratory irritation of 25 ppm, whereas exposure to much (20x) higher levels of ammonia (500 ppm) were without effect on biochemical parameters. It is therefore concluded that protection against the local effects of ammonia will be significantly protective of any potential systemic effects.

Inhalation DNEL:

The critical inhalation effect is local irritation of the respiratory tract

For short-term exposures, ammonia at levels of 50 ppm (36 mg/m³) was tolerated without signs of definite irritation. Applying an assessment factor of 5 to cover intraspecies (general public) variation results in a short-term inhalation (local) DNEL of 7.2 mg/m³.

A NOAEL of 20 ppm (14 mg/m³) for long-term exposure is derived from the weight of evidence from the human studies. Applying an assessment factor of 5 to cover intraspecies (general public) variation results in a long-term inhalation (local) DNEL of 2.8 mg/m³.

A DNEL for systemic effects following inhalation is derived from the 4 -week toxicity and developmental toxicity screening test with diammonium phosphate (DAP). The NOAEL in this study of 250 mg/kg bw/d DAP is equivalent to 68 mg/kg bw/d ammonia. Assuming a bodyweight of 70 kg, this is equivalent to 4.76 g ammonia/day. It is notable that this level of exposure is less than the total amount of ammonia generated in the body (~20 g/day) and is approximately equal to the amount of ammonia produced by intestinal bacteria. Applying the standard assessment factors recommended under REACH would result in the generation of a DNEL value equivalent to a very small proportion (<1%) of the quantity of ammonia normally produced by the body's metabolic processes and is considered to be excessively conservative. For this substance, therefore, an assessment factor of 10 is applied (6.8 mg/kg bw/d, equivalent to 476 mg/day). The maximum exposure to ammonia therefore represents approximately 10% of the quantities normally generated by the gastrointestinal tract bacteria and is approximately 3% of the total amount of ammonia produced daily by the body.

Assuming a breathing rate of 20 m³/day a short-term inhalation (systemic) DNEL of 23.8 mg/m³ is calculated. Given that this small additional exposure to ammonia is readily detoxified by normal homeostatic mechanisms, the same value of 23.8 mg/m³ is proposed for long-term inhalation (systemic) DNEL.

Dermal DNEL:

The substance is corrosive, therefore dermal exposure should be avoided by the use of PPE and engineering controls. A DNEL for systemic effects is derived from the 4-week toxicity and developmental toxicity screening test with DAP, in which a NOAEL of 250 mg/kg bw/d (68 mg/kg bw/d ammonia) was derived. Using the same logic as described above, a non-standard assessment factor of 10 is applied. The dermal absorption of ammonia is likely to be very low (IPCS, 1990); a dermal absorption value of 10% is assumed for the purposes of DNEL derivation for the general population who will not be exposed to corrosive concentrations of ammonia. As described above, no additional (duration) factors are required for the derivation of a long-term dermal DNEL.

A short-term and long-term dermal DNEL value of 68 mg/kg bw/d is therefore derived. As noted above, the nature of the substance is such that local effects are predicted at exposure levels below those causing systemic effects by this route, and therefore the dermal DNEL for local effects will be protective.

Oral DNEL

The critical NOAEL is 250 mg/kg bw/d diammonium phosphate (equivalent to 68 mg/kg bw/d ammonia) from the 4 -week toxicity and developmental toxicity screening test. Using the same logic as described above, a non-standard assessment factor of 10 is applied, resulting in a DNEL of 6.8 mg/kg bw/d.