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Appendices 1-18 to: Report on the Health Effects of Selected Pesticide Coformulants
13 Summary
13.1 Description
13.2 Toxicokinetics
13.3 Human toxicity
13.3.1 Single dose toxicity
13.3.2 Repeated dose toxicity
13.3.3 Toxicity to reproduction
13.3.4 Mutagenic and genotoxic effects
13.3.5 Carcinogenic effects
13.4 Animal toxicity
13.4.1 Single dose toxicity
13.4.2 Repeated dose toxicity
13.4.3 Toxicity to reproduction
13.4.4 Mutagenic and genotoxic effects
13.4.5 Carcinogenic effects
13.1 Description
Diammonium sulphate occurs as colourless orthorhombic crystals or white granules with no odour. The water solubility is high (754-770 g/l).
13.2 Toxicokinetics
When hamsters inhaled diammonium sulphate at a concentration of 0.2 mg/m3, a substantial proportion of the compound was found in the nose. The clearance from the lungs was determined to be about 20 minutes. The results of clearance studies with guinea pigs and rabbits suggested that there was no species difference.
Systemic effects and death following oral exposure to diammonium sulphate indicate that it may be absorbed from the gastrointestinal tract.
Acute intoxication with ammonium may affect the cerebral nervous system by inhibition of the energy metabolism or by inhibition of glutamic acid metabolism.
13.3 Human toxicity
13.3.1 Single dose toxicity
In several studies healthy and asthmatic non-smoking volunteers aged 18-76 have been exposed by inhalation to diammonium sulphate aerosols in concentrations between 0.07 and 1.0 mg/m3 (and with MMAD of 0.5-1 mm) for up to 4 hours. In some of the studies diammonium sulphate was administered in combination with ozone, sulphur dioxide or carbachol (a known bronchoconstrictor). In all studies different measurements of pulmonary function was performed. In doses up to 0.5 mg/m3 consistent changes in pulmonary function or in symptoms occurred in neither healthy nor asthmatic volunteers. At a concentration of 1 mg/m3, diammonium sulphate produced a small but significant decrease in flow rates on maximum and partial expiratory flow-volume curves and potentiated the bronchoconstrictor action of carbachol both in asthmatic and healthy volunteers.
The effect of exposure to a combination of ozone and diammonium sulphate seemed slightly greater (although not statistically significant) than exposure to ozone alone. The combination of diammonium sulphate and sulphur dioxide produced no significant changes on the lung function at the doses studied. Upper respiratory and eye irritation was reported in one of the studies in some of the volunteers exposed to 0.5 mg/m3 of diammonium sulphate.
One case-report of death caused by acute intoxication due to ingestion of diammonium sulphate exists.
13.3.2 Repeated dose toxicity
No consistent changes in pulmonary function or in symptoms occurred in healthy or asthmatic men when exposed to diammonium sulphate aerosols at a concentration of 0.1 mg/m3 (MMAD = 0.3 mm) for 2 hours a day for 2-3 days.
13.3.3 Toxicity to reproduction
No data have been found.
13.3.4 Mutagenic and genotoxic effects
No data have been found.
13.3.5 Carcinogenic effects
No data have been found.
13.4 Animal toxicity
13.4.1 Single dose toxicity
The reported LC50-value (exposure duration: 8 hours) of diammonium sulphate is higher than 1200 mg/m3 (particle size averaged 2-3 mm) for rats and higher than 900 mg/m3 (particle size not stated) for guinea pigs. The LD50-value following oral exposure is reported to be 2840-4250 mg/kg b.w. for rats and 610-640 mg/kg b.w. for mice. Three rabbits dosed with 1500 mg/kg b.w. of diammonium sulphate through a gastric probe all died.
The airway responsiveness to inhaled carbachol (a known bronchoconstrictor) was enhanced in sheep exposed to 0.1 or 4 mg/m3 of diammonium sulphate with a MMAD of 1.5 mm (but not of 0.5 mm) for 4 hours.
The bronchiolar or tracheal mucociliary clearance was not affected either in donkeys, rats, rabbits, or sheep inhaling diammonium sulphate aerosols for 1-4 hours in doses of 0.3-3.6 mg/m3.
Diammonium sulphate was not irritating to intact or abraded rabbit skin or to rabbit eyes.
13.4.2 Repeated dose toxicity
Pulmonary histology
In rats exposed to 0.5 mg/m3 (MMAD = 0.44 mm), the authors were mainly concerned about the increased alveolar fibrosis observed after 8 months of exposure (but not after 4 months of exposure or after 3 months of recovery). Increased alveolar collagen content was also observed in rats and guinea pigs exposed to 1 mg/m3 (MMAD = 0.4 mm) for 20 days.
A significant increase in alveolar cord length was observed in rats exposed to 0.5 mg/m3 (MMAD = 0.44 mm) for 4 months (but not after 8 months of exposure) and after 3 months of recovery. Increased alveolar cord length was also observed in rats and guinea pigs exposed to 1 mg/m3 (MMAD = 0.4 mm) for 20 days.The number of non-ciliated epithelial cells in the bronchioles increased in rats exposed to 0.5 mg/m3 (MMAD = 0.44 mm) for 4 and 8 months (but not after recovery). Guinea pigs (but not rats) exposed to 1 mg/m3 (MMAD = 0.4 mm) for 20 days, had hypertrophy and hyperplasia of non-ciliated epithelial cells in the alveoli and bronchioles.
No significant changes could be detected in histological examination of the trachea, bronchial lymph nodes and lungs of rats, which had been exposed to 300 mg/m3 of diammonium sulphate aerosols (particle size averaged 1-2 mm) for 1-14 days. Rats exposed to 1 or 5 mg/m3 (MMAD = 0.5-0.6 mm) of diammonium sulphate aerosols for 2-7 days did not show any histological changes of the lungs either.
Pulmonary function
The pulmonary function of rats exposed for 4 months to 0.5 mg/m3 (MMAD = 0.44 mm) of diammonium sulphate was significantly decreased for a few measured parameters (residual volume/total lung capacity, quasistatic compliance, nitrogen-slope).
Rats exposed to 1.0 mg/m3 (MMAD = 0.4 mm) of diammonium sulphate aerosols for 20 days had increased values of residual volume and functional residual capacity and a decreased nitrogen-slope.
No significant changes could be detected in pulmonary function of rats, which had been exposed to 300 mg/m3 of diammonium sulphate aerosols (particle size averaged 1-2 mm) for 1-14 days or in guinea pigs exposed for 20 days to 1.0 mg/m3 (MMAD = 0.4 mm).
Interactions
Diammonium sulphate exposure at 0.5-1.0 mg/m3 aggravated the effects induced by elastase pre-treatment in the rats exposed for 20 days, 4 months and 8 months. A synergistic effect of the combination of ozone and diammonium sulphate was observed in rats exposed to diammonium sulphate for 2-7 days at a concentration of 5 mg/m3 (but not at 1 mg/m3) (MMAD = 0.5-0.6 mm). The degree of asthmatic dyspnoea (immediate type induced by inhalation of albumin) was dose-dependently increased in guinea pigs exposed to 0.2-2.0 mg/m3 (MMAD = 0.7-0.9 mm) diammonium sulphate aerosols (only significant at 2 mg/m3) for 7½ weeks.
Immunological studies of peripheral lymphocytes and spleen cells of rats exposed to 0.5 mg/m3 (MMAD = 0.44 mm) of diammonium sulphate for 4 months revealed no significant depressive effects on the immune system.
Diarrhoea in the males at the highest dose was the only observed effect in rats fed diammonium sulphate in their diet in doses up to 1975 mg/kg b.w. per day for 13 weeks.
13.4.3 Toxicity to reproduction
No data have been found.
13.4.4 Mutagenic and genotoxic effects
Diammonium sulphate tested negative in Ames tests and in a yeast gene mutation assay with and without metabolic activation systems, and in cytogenetic assays in V79 hamster cells, in human lymphocytes, and in CHO cells.
Addition of diammonium sulphate increased the mutagenicity of a known mutagen (ethylmethanesulphonate).
13.4.5 Carcinogenic effects
Diammonium sulphate inhaled by hamsters at a concentration of 0.2 mg/m3 for 15 weeks did not affect the carcinogenic potential of the known carcinogen benzo(a)pyrene.
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