This CICAD on manganese and its compounds was based principally on the report entitled Toxicological profile for manganese (update), draft for public comment, prepared by the Agency for Toxic Substances and Disease Registry, US Department of Health and Human Services (ATSDR, 1996). Information contained in the Hazardous Substances Data Bank, developed and maintained by the National Library of Medicine, US Department of Health and Human Services, was also used (HSDB, 1998). Data identified as of November 1998 were considered in these source documents. Additional data came from other references, such as assessments prepared by the US Environmental Protection Agency (EPA) and the World Health Organization (WHO), as well as a variety of reports in the literature. The source documents used to develop this CICAD do not cover the effects of manganese on the ecological environment. No other sources (documents developed by a national organization and subject to rigorous scientific review) on this topic were identified. Therefore, this CICAD addresses environmental levels as a source of human exposure only. No attempt has been made in this document to assess effects on organisms in the environment. Information on the availability of the source documents is presented in Appendix 1. Information on the peer review of this CICAD is presented in Appendix 2. This CICAD was approved as an international assessment at a meeting of the Final Review Board, held in Berlin, Germany, on 26-28 November 1997. Participants at the Final Review Board meeting are presented in Appendix 3. The International Chemical Safety Card (ICSC 0174) for manganese, produced by the International Programme on Chemical Safety (IPCS, 1993), has also been reproduced in this document. Manganese (Mn) is a naturally occurring element that is found in rock, soil, water, and food. Thus, all humans are exposed to manganese, and it is a normal component of the human body. Food is usually the most important route of exposure for humans. Estimated Safe and Adequate Daily Intakes of 1-5 mg manganese have been established for children 1 year of age and older through to adults; these levels generally parallel amounts of the compound delivered via the diet. Manganese is released to air mainly as particulate matter, and the fate and transport of the particles depend on their size and density and on wind speed and direction. Some manganese compounds are readily soluble in water, so significant exposures can also occur by ingestion of contaminated drinking-water. Manganese in surface water can oxidize or adsorb to sediment particles and settle to the bottom. Manganese in soil can migrate as particulate matter to air or water, or soluble manganese compounds can be leached from the soil. Above-average exposures to manganese are most likely to occur in people who work at or live near a factory or other site where significant amounts of manganese dust are released into the air. In some regions, the general population can be exposed to manganese released into air by the combustion of unleaded gasoline containing the organomanganese compound methyl-cyclopentadienyl manganese tricarbonyl (MMT) as an antiknock ingredient. Some people can be exposed to excess manganese in drinking- water - for example, when manganese from batteries or pesticides leaches into well-water. Children can be exposed to excess manganese in soils through hand-to-mouth behaviour. In humans, manganese is an essential nutrient that plays a role in bone mineralization, protein and energy metabolism, metabolic regulation, cellular protection from damaging free radical species, and the formation of glycosaminoglycans. However, exposure to high levels via inhalation or ingestion can cause adverse health effects. Given comparable doses, more manganese reaches the brain following inhalation than following ingestion, and most health effects are associated with chronic inhalation exposure. Little is known about the relative toxicity of different manganese compounds. However, available evidence indicates that various manga ese compounds can induce neurological effects; these effects have been observed following chronic (365 days or more) inhalation exposures in humans and intermediate (15-364 days) and chronic oral exposures in animals. In general, the available data indicate that exposure to excess manganese for 14 days or less (acute duration) or up to a year (intermediate duration) has an effect on the respiratory system and the nervous system, with little to no effect on other organ systems. Acute inhalation exposure to high concentrations of manganese dusts (specifically manganese dioxide [MnO2] and manganese tetroxide [Mn3O4]) can cause an inflammatory response in the lung, which, over time, can result in impaired lung function. Lung toxicity is manifested as an increased susceptibility to infections such as bronchitis and can result in manganic pneumonia. Pneumonia has also been observed following acute inhalation exposures to particulates containing other metals. Thus, this effect might be characteristic of inhalable particulate matter and might not depend solely on the manganese content of the particle. There are a few reports suggesting that intermediate inhalation exposure to manganese compounds produces effects on the central nervous system, but reliable estimates of exposure levels are not available. Inhalation studies in animals resulted in biochemical, respiratory, and neurobehavioural effects. However, a threshold for these effects has not been identified, because the exposure levels associated with these effects range over an order of magnitude. In chronic inhalation exposure to manganese, the main organ systems affected are the lungs, nervous system, and reproductive system, although effects on other organ systems have also been observed. A recurring manganic pneumonia and acute respiratory effects have been associated with chronic inhalation exposures to manganese. Effects on the nervous system include neurological and neuropsychiatric symptoms that can culminate in a Parkinsonism-like disease known as manganism; evidence suggests that laboratory animals, especially rodents, are not as sensitive as humans, and possibly other primates, to the neurological effects of inhalation exposure to manganese. Reproductive effects of chronic inhalation exposure to manganese include decreased libido, impotence, and decreased fertility in men; information is not available on reproductive effects in women. Studies in animals indicate that manganese can cause direct damage to the testes and late resorptions. Data from animal studies on the effects of inhaled manganese on the immunological system and the developing fetus are too limited to make firm conclusions on the significance of these effects for humans. Information on the carcinogenic potential of manganese is limited, and the results are difficult to interpret with certainty. In rats, chronic oral studies with manganese sulfate (MnSO4) showed a small increase in the incidence of pancreatic tumours in males and a small increase in pituitary adenomas in females. In other studies with manganese sulfate, no evidence for cancer was noted in rats and a marginally increased incidence of thyroid gland follicular cell adenomas was observed in mice. The results of in vitro studies show that at least some chemical forms of manganese have mutagenic potential. However, as the results of in vivo studies in mammals are inconsistent, no overall conclusion can be made about the possible genotoxic hazard to humans from exposure to manganese compounds. Large oral doses of concentrated manganese salts given by gavage can cause death in animals, but oral exposures via food or water have not been found to cause significant toxicity over acute or short-term exposures. Similarly, parenteral administration of manganese salts can cause developmental toxicity, but effects were not found with oral exposure. Intermediate-duration oral exposure to humans to manganese has been reported to cause neurotoxicity in two cases, but the data are too limited to define the threshold or to judge if these effects were due entirely to the manganese exposure. Some data on neurological or other health effects in humans from chronic oral intake of manganese exist, but these studies are limited by uncertainties in the exposure routes and total exposure levels as well as by the existence of other confounding factors. The studies in humans and animals do not provide sufficient information to determine dose levels or effects of concern following chronic oral exposure. Thus, the available evidence for adverse effects associated with chronic ingestion of excess manganese is suggestive but inconclusive. The dermal route does not appear to be of significant concern and has not been investigated to any extent. Available information is limited to reports on the corrosive effects of potassium permanganate (KMnO4) and case reports of effects from dermal absorption of organic manganese compounds such as MMT. From these data, it is clear that adverse neurological and respiratory effects from manganese exposure can occur in occupational settings. Limited evidence also suggests that adverse neurological effects can be associated with ingestion of excess manganese in environmental settings. As a result of predisposing factors, certain individuals might be more susceptible to adverse effects from exposure to excess manganese. These might include people with lung disease, people who are exposed to other lung irritants, neonates, older people, individuals with iron deficiency, or people with liver disease.