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SIDS INITIAL ASSESSMENT PROFILE

CAS Nos. 7664-41-7; 1336-21-6; 7783-18-8; 12593-60-1

Chemical Names Ammonia category : ammonia, aqueous ammonia, ammonium thiosulfate, ammonium phosphate sulfate

Structural Formula NH 3 ; NH 4 OH; (NH 4 ) 2 S 2 O 3 ; (NH 4 ) 2 H 2 PO 4 HSO 4

SUMMARY CONCLUSIONS OF THE SIAR

Category Rationale

The ammonia category includes anhydrous ammonia, aqueous ammonia, ammonium thiosulfate and ammonium phosphate sulfate. In biological fluids and in aquatic environments, every substance of the category will dissociate to yield, respectively; ammonium ion (NH 4 + ), hydroxide ion ( - OH), thiosulfate ion (S 2 O 3 2- ), phosphate ion (H 2 PO 4 - ) and sulfate ion (SO 4 2- ). Each of the compounds of the category contains the ammonia/ammonium ion functional group. The sulfate, thiosulfate and phosphate ions are normal constituents of the blood, and when in excess, are excreted via the urine. Among these compounds, un-ionized ammonia is considered the most toxic and is the basis for read-across for the category members.

The category is based on the dissociation of all the category members into the ammonium ion (NH 4 + ) and the corresponding anions in aqueous environments, where the ammonia/ammonium ion will exist in equilibrium between NH 3 and NH 4 + , depending on the pH. At ambient environmental conditions, the category members are stable substances that show normal acid/base chemical activity with the following equilibria:

NH 4 + + H 2 O  3 + H 3 O +

NH 3 + H 2 O  4 + + OH Thus for many environmental conditions (pH =5 to 8), the predominant form will be NH 4 + . At pH =9 the ratio of ammonia to ammonium ion (NH 3 / NH 4 + ) should approach unity; at higher pHs the proportion of ammonia (NH 3 ) should increase. As inorganic salts that ionize in the aquatic environment, the category members can be considered chemically and structurally similar for the purposes of this category evaluation. As pH decreases, the concentration of ammonium ion increases with respect to decreases of unionized ammonia concentrations. However, the toxicity of the unionized ammonia is considered several orders of magnitude greater than the more abundant ammonium ion. The ammonium ion toxicity is considered to contribute to the overall toxicity.

Analog Rationale

Data for ammonium sulfate (SIAM 19; CAS No. 7783-20-2), sodium sulfate (SIAM 20; CAS No. 7757-82-6), ammonium chloride (SIAM 17; CAS No. 12125-02-9), sodium thiosulfate (CAS No.

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7772-98-7) and di-ammonium phosphate (SIAM 24; CAS No. 7783-28-0) are used to fill the data gaps for SIDS endpoints. These substances all dissociate to their respective cations and anions at physiological pH, whose data are used to support the respective cations or anions of the category

members.

Human Health

After uptake into a biological system the salts in the ammonia category will dissociate directly into ammonium ion and the corresponding anions, i.e. phosphate, thiosulfate and sulfate. The anions will enter the body electrolyte pool, and are not expected to play a significant toxicological role at low doses. After intestinal absorption, ammonium ions are converted to urea in the liver, and subsequently excreted in urine (within 6 hours). The ratio of ammonium ion to neutral ammonia is about 100 in blood of normal pH range.

The acute oral LD 50 values range from 1,950 to >2,000 mg/kg bw in rats for the ammonium salts. Aqueous ammonia has a higher oral toxicity (LD 50 of 350 mg/kg bw in rat) than the other compounds in the group. Clinical signs include sedation, staggering, abnormal posture, convulsions, tremors, ataxia, prostration, ptosis, exophthalmus, chromodacryorrhea, unilateral ocular opacity, salivation, labored and irregular breathing and diarrhea. Acute dermal LD 50 values are >2,000 mg/kg bw for ammonium sulfate and diammonium phosphate (DAP). The inhalation LC 50 values range from >900 mg/m 3 for ammonium sulfate (guinea pig) to 13,770 mg/m 3 for ammonia (rat). Clinical signs observed after inhalation include eye irritation, labored breathing and nasal discharge, pulmonary hemorrhages. Ammonia concentrations of 348-6953 mg/m 3 may lead to death in humans. The LD 50 and LC 50 values are taken from studies whose reliability rating is a 4 (unassignable) and whose data are used on a weight of evidence basis.

Aqueous ammonia is corrosive to skin and eyes in animal studies and humans due to the high pH. The ammonium salts are slightly irritating to skin and moderately irritating to eyes in animal studies. In humans, slight respiratory irritation was observed at 50 mg/m 3 ammonia and at 1 mg/m 3 concentrations of ammonium sulfate, pulmonary function was affected. No data are available on the sensitization potential of the category members. However, human data suggest that DAP may be sensitizing to the respiratory tract. In repeated-dose inhalation studies, with ammonia (rats) and aqueous ammonia (rats, rabbits, guinea pigs and dogs), the main effects observed are irritation, and inflammation of the respiratory tract at 105 mg/m 3 and above. For ammonia, the NOAEL of 6.4 mg/m 3 was determined based on an occupational study and the lack of evidence of decreased pulmonary function or changes in subjective symptoms. No LOAEL was established. In rats, the LOAEL was determined to be 17.4 mg/m 3 based on increased severity of rhinitis and pneumonia with respiratory lesions. A NOAEL was

not established.

For ammonium sulfate, inhalation studies in rats showed respiratory effects (enlarged alveoli, alveolar ducts and sacs) at 1 mg/m 3 . In a semi-chronic study [input exposure duration], enhanced bronchiolar cell hyperplasia and fibrosis were reported at 0.5 mg/m 3 . In a sub-chronic inhalation study with rats, exposure to 26.8 mg/m 3 of ammonium thiosulfate resulted in systemic effects such as growth reduction, increased levels of acid and alkaline phosphatase, effects on calcium, CNS effects and cardiovascular changes.

In a 13 week repeated-dose feeding study in rats given ammonium sulfate up to 1,975 mg/kg bw/day, no effects were observed on body weight, food consumption or hematological and clinical parameters. However, increased kidney weights (in males and females) and increased liver weights (females) were observed at the highest dose without histopathological changes. The NOAEL was 1,975 mg/kg bw/dayfor females and 886 mg/kg bw/day for males (diarrhea). In a combined repeateddose/reproduction/developmental oral gavage screen ing study in rats exposed to 0. 250, 750 and 1,500 mg/kg bw DAP for 35 days, a NOAEL of 250 mg/kg bw was derived based on increased alkaline phosphatase and decreased total protein in blood.

Ammonia, ammonium thiosulfate and the analogues ammonium sulfate and DAP did not induce effects in tests on gene mutations and chromosomal aberrations. Ammonium sulfate was negative, in vivo, when tested for chromosomal effects. Ammonia is not carcinogenic when administered to rats in thedrinking water. However, ammonia did have promoting effects in gastric cancer induced by N-methylN’-nitro-N-nitrosoguanidine 

### ( MMNG). Ammonium sulfate showed no promoting effect.

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No histopathological changes to the reproductive organs were found in repeated-dose toxicity studies with ammonium sulfate. No effects on reproduction and development were found in studies with ammonia (at 24.3 mg/m 3 ). In a reproduction/developmental toxicity screening test (similar to OECD 422) rats (5 males and 10 females/group) were administered DAP by oral gavage at doses of 0, 250, 750 and 1,500 mg/kg bw/day. Animals were exposed two weeks prior to mating, during mating (both sexes) and for an additional three and a half weeks through gestation until lactation day 4 (females). No effects on reproduction were reported up to 1,500 mg/kg bw/day. No developmental effects were observed up to 1,500 mg/kg bw/day. The NOAEL for reproductive and developmental toxicity for DAP was 1,500 mg/kg bw.

Environment

The melting points for ammonia, aqueous ammonia, ammonium thiosulfate, and ammonium phosphate sulfate are

-78 o C, -77 o C, 150 o C, and 235 o C, respectively. The boiling points are -33 o C, 36 o C, for ammonia and aqueous ammonia, respectively, while ammonium thiosulfate and ammonium phosphate sulfate decompose at 150 o C and

>235 o C, respectively. The vapor pressure for ammonia is 8611hPa at 20 o C; aqueous ammonia, 2878hPa at 25 o C; ammonium thiosulfate, 18 mm Hg at 70 o F (21.1 o C), and ammonium phosphate sulfate – (not applicable). The water solubility for the category substances is in the range of 430 to > 1000 g/L at 20 o C. The pH for ammonia is 10.6-11.6 (0.01-1%) at 25 o C and aqueous ammonia is expected to be similar. The pKa for ammonia is 9.25. Ammonium thiosulfate (200 g/L at 20 o C) and ammonium phosphate sulfate (10% solution in water) pH values are in the range of

6.5-7.2 and 4.5-5.5 o C, respectively.

All substances from the ammonia category are very soluble in water and dissociate upon release into water. Anhydrous and aqueous ammonia are volatile. Ammonia toxicity depends on the pH and temperature of the media, as well as the amount of ammonia already present. Increasing pH, and temperature to a lesser degree, results in the presence of more un-ionized ammonia (percentage of total ammonia present as NH3 in aqueous solutions at 20 o C is 0.039% at pH 6 and 3.82% at pH 8).

Upon application of ammonium fertilizers, ammonium can be taken up by plants or adsorbed onto clay particles in the soil. Leaching or run-off may occur via cation exchange dependent on soil texture, clay content, pH and ionic strength of the irrigation water. Soil bacteria may convert ammonium to nitrate. Nitrate can be taken up by plants or denitrified again to yield nitrogen and nitrous oxide gas. Ammonia may also directly volatilize from the soil. Transport via the atmosphere will mainly be due to diffusion and air concentrations will decrease quickly with increasing distance from the source. Ammonium ion and the anions from the substances of the ammonia category are all subject to nitrification. The fate and behaviour of the substances, such as bioaccumula tion, are also closely related to nitrogen cycles in air, soil and water. In anaerobic environments, sulfate is biolog ically reduced to (hydrogen) sulfide by sulfate reducing bacteria, or incorporated into living organisms as a source of sulfur, and thereby included in the sulfur cycle. In acidic aqueous environments, thiosulfate is similarly expected to di ssociate to sulfur and sulfur dioxide and enter the sulfur cycle and/or the atmosphere. Phosphate salts released into the environment will be distributed between water and soil. Land-applied phosphate and ammonium are adsorbed to soil particles. In water the phosphate salts may result in eutrophication (caused by ammonium and phosphate ions), which may lead to increased algal growth. Decomposition of the algae may in turn result in lower dissolved oxygen concentrations. If dissolved oxygen concentrations are lowered significantly, suffocation of other aquatic organisms may occur.

LC 50 values for fish toxicity range between 6.9 and 175 mg total NH3/L for the ammonium substances dependent on pH and temperature during the test. Long-term exposure of fish to ammonium compounds may induce reproductive changes starting at 100 mg/L. EC 50 values for invertebrates range from 21.8 mg total NH3/L for ammonium chloride to > 25.7 mg total NH3/L for ammonium sulfate. Long-term studies with invertebrates showed slightly lower NOEC values of 3.1-3.47 mg total NH3/L. The algae Chlorella vulgaris EC 50 (biomass; 0-5d) was 1300mg/L using ammonium chloride). In a 21-day test with Chlorella vulgaris and ammonium sulfate, an EC 50 of 25,476 mg/L (2700 mg N/L) was established from exponential growth on day 11-18. Ammonia that is unionized is toxic to aquatic organisms at concentrations below 1 mg/L.

Exposure

For the year 2004 the global market for the ammonia category was estimated to be ca. 65,000 ktonnes. For the United States (Sponsor country) production was estimated at 9 ktonnes. The substances are mainly used as intermediates in the production of fertilizers, fibers and plastics, explosives, solvents and household cleaning products. Environmental exposure occurs through naturally occurring mechanisms whereby microorganisms break down organic nitrogen products such as urea and proteins found in manure as well as via the use of fertilisers and household cleaning

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products. According to the information in the USEPA Toxics Release Inventory database for 2004, the total reported emissions of ammonia were 171,179,218 lbs (77,647 tonnes).

Occupational exposure may occur during the production, transportation and processing of ammonia containing compounds. Field exposure to workers is possible during use as fertilizers via both the dermal and inhalation routes of exposure. A generic Threshold Limit Value (TLV) of 10 mg/m3, as a nuisance dust, exists for the solids of the ammonia category. The Occupational Safety and Health Administration (OSHA) has set a Permissible Exposure Limit (PEL) of 50 ppm (35 mg/m3) averaged over 8 hours for ammonia and 15 mg/m3 for sodium thiosulfate. The National Institute for Occupational Safety and Health (NIOSH) has recommended an airborne exposure limit of 25 ppm (18 mg/m3) averaged over a 10 hour period and not to exceed 35 ppm (27 mg/m3) during any 15 minute work period for ammonia. Similarly, the American Conference of Governmental Industrial Hygienists (ACGIH) has recommended a 25 ppm (18 mg/m3)airborne exposure limit averaged over 8 hours with a short term exposure limit (STEL) of 35 (27 mg/m3)ppm.

Consumer exposure can occur during the use of cleaning products and fertilizers.

RECOMMENDATIONS AND RATIONALE FOR THE RECOMMENDATION

AND NATURE OF FURTHER WORK RECOMMENDED

Human Health: The chemicals are currently of low priority for further work. The chemicals possess hazards for human health (irritant to corrosive, acute toxicity). Based on data presented by the Sponsor country, adequate risk management measures are being applied. Countries may desire to check their own risk management measures to find out whether there is a need for additional measures. In the environment, ammonia degrades to nitrite. It is recommended that the use of the chemicals as fertilizers be taken into account when assessing the exposure of nitrite and nitrate to humans through drinking water.

Environment: The chemicals are currently of low priority for further work. The chemicals possess properties indicating a hazard to the environment (acute aquatic EC/LC 50 values between 1 and 100 mg/L). Unionized ammonia toxicity to aquatic organisms is reported at < 1 mg/L. The pH and temperature of water bodies can affect the EC/LC 50 values. The chemicals are of low priority for further work for the environment because of their rapid nitrification. Ammonia has indirect and long-term effects on ecosystems, e.g. eutrophication, groundwater pollution and soil

acidification due to the nitrification of ammonia.