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Appendices 1-18 to: Report on the Health Effects of Selected Pesticide Coformulants

5   Regulations

5.1   Ambient air

Denmark (C-value):         0.001 mg Mn/m³ (MST 2002).

WHO (2000):                 0.00015 mg Mn/m³.

US-EPA (1993):             RfC 0.00005 mg Mn/m³ (IRIS 2000).

5.2   Drinking water

Denmark:                        0.05 mg Mn/l (MM 2001).

WHO (1996):                 0.5 mg Mn/l.

US-EPA (1993):             0.05 mg Mn/l (HSDB 2000).

5.3   Soil

Denmark:                        -

The Netherlands:             -

5.4   Occupational Exposure Limits

Denmark:                        0.2 mg Mn/m³ (At 2002).

ACGIH:                          0.2 mg Mn/m³ (HSDB 2000).

The occupational exposure limits in different countries around the world varies between 0.2 and 5 mg Mn/m³ (IRIS 2000).

5.5   Classification

Manganese sulphate is classified for effects following repeated exposure (Xn;R48/20/22 - harmful: danger of serious damage to health by prolonged exposure through inhalation and if swallowed) and for environmental effects (N;R51/53 – toxic to aquatic organisms, may cause long-term adverse effects in the aquatic environment). (MM 2002).

5.6   IARC

-

5.7   US-EPA

Manganese is not classifiable with regard to human carcinogenicity (Group D) (EPA 1993b – quoted from ATSDR 2000).

5.8   ATSDR

Minimal risk level (MRL): 0.00004 mg Mn/m³ (chronic inhalation).

 6   Summary 6.1   Description

Manganese sulphate and manganese sulphide occur as powders or crystals of several hydrates. Manganese sulphate has a high water solubility (greater than 500 g/l) at room temperature, while manganese sulphide is insoluble in water. In moist conditions, manganese sulphide readily oxidizes in air to the sulphate.

Manganese is a natural component of the environment and an essential element in the nutrition of humans and animals.

6.2   Toxicokinetics

Manganese absorption occurs primarily through the diet. Of ingested inorganic manganese about 3-5% is absorbed in humans. The absorption is influenced by such factors as the water solubility of the compounds in ques­tion, age, and the amount of manganese as well as of other trace elements such as iron, calcium and phosphorus present in the gut. Absorption via the lungs can be significant for occupationally exposed persons or for those exposed to excess levels of airborne manganese. The absorption following inhalation is higher than that after oral administration for the more soluble forms of inorganic manganese.

In healthy humans, manganese is distributed to the tissues with the highest levels found in the liver, pancreas, and kidney and the lowest levels in bone and fat.Excess manganese (following oral exposure in humans with liver diseases) was accumulated in certain regions of the brain (basal ganglia, especially the globus pallidus and the substantia nigra).
Mice and rats chronically fed manganese sulphate generally had elevated tissue levels of manganese. The manganese levels in the liver and kidney were higher than the levels in the brain.

Following inhalation in rats, most manganese was distributed to the olfactory bulb and the brain but also to other organs such as the lungs, the liver, the kidneys, and the pancreas. One study indicates that manganese may be distributed directly to the brain from the nasal cavity via the olfactory pathway by-passing the blood-brain barrier. Preferential accumulation of manganese in specific locations of the brain (including the caudate nucleus, globus pallidus, and the substantia nigra) was noted in one monkey exposed to an aerosol of manganese chloride several hours/day for 3-5 months.

Manganese is excreted with a half-life of 13-37 days in humans. In general, biliary excretion is the main pathway by which absorbed manganese reaches the intestines where most of the element is excreted in the faeces.
An inhalation study in monkeys showed that a portion of the manganese was retained in the lung and brain and was cleared with a half-life of up to 250 days. Small amounts of manganese can also be found in urine, sweat, and milk.The central nervous system is the primary target of manganese toxicity. Several hypotheses have been proposed for the toxicological mechanism behind this toxicity.

6.3   Human toxicity

6.3.1   Single dose toxicity

No data were found.

6.3.2   Repeated dose toxicity

From studies of humans exposed to manganese dusts (mainly manganese dioxide) in mines and factories, clear evidence exist that inhalation exposure to high levels of manganese for longer periods can lead to neurological effects. The disease, termed manganism, is characterised by weakness, muscle rigidity, tremor, apathy, speech disturbances, a mask-like face, and slow clumsy movement of the limbs typically after several years of exposure but some individuals may begin to show signs after as few as 1-3 months of exposure. In most cases the symptoms are irreversible. People with manganism generally have significantly poorer eye-hand coordination, hand steadiness, reaction time and postural stability, and a lower level of performance in cognitive flexibility on neurobehavioral tests.

Recent epidemiological data indicate that concentrations of manganese in respirable dust in the range of 0.027 to 0.215 mg Mn/m³ and in total dust in the range of 0.14 to 1.59 mg Mn/m³ in the workplace can result in measurable neurological effects.

Occupational studies indicate that manganese inhaled in high concentrations may elevate the serum prolactin and cortisol levels, lower the blood pressure, and cause inflammation in the lungs.

Only limited evidence exist that oral exposure to excess manganese in humans leads to neurological effects similar to those reported for inhalation exposure.

6.3.3   Toxicity to reproduction

Decreased libido and impotence are common symptoms in male workers with clinical signs of manganism following exposure to high levels of manganese dusts. In addition increased semen liquefaction time, decreased sperm count, decreased sperm viability, and decreased fertility have been reported in some studies.

Two studies of school children showed that increased oral exposure to manganese in drinking water and food was associated with poorer performance in school and on neurobehavioral tests as compared to children exposed to lower levels. However, the children may have been exposed to other metals that may have influenced the developmental effects seen.

Incidences of stillbirths and malformations have been studied in an Australian aboriginal population living on an island where environmental levels of manganese are high. However, data from a suitable control group are lacking.

6.3.4   Mutagenic and genotoxic effects

An increase in chromosomal aberrations was found in a group of workers, which had been exposed to a mixture of manganese, nickel, and chromium by inhalation for 10-24 years.

6.3.5   Carcinogenic effects

No data were found.

6.4   Animal toxicity

6.4.1   Single dose toxicity

Acute inhalation exposure to high concentrations of manganese dusts can cause an inflammatory response in the lung. Oral doses of manganese salts given by gavage can cause death in animals.

6.4.2   Repeated dose toxicity

Oral and inhalation studies in animals exposed to manganese have sometimes revealed biochemical or neurobehavioral evidence of neurological effects. Monkeys exposed to manganese via inhalation, oral intake or injection exhibit neurological symptoms very similar to those observed in workers exposed to manganese. They accumulate manganese in the basal ganglia, as do humans exposed to excess manganese. However, motor deficits similar to clinical effects in humans are seldom observed in rodents and tend to be transient effects.

Animal studies indicate that manganese inhaled in high concentrations may cause inflammation in the lungs. Mice and/or rats exposed orally to high doses of manganese sulphate for 2 years may experience gastrointestinal (e.g. hyperplasia and erosion of the forestomach), renal (increased severity of chronic progressive nephropathy) and/or endocrine (thyroid follicular hyperplasia and dilation) effects.

6.4.3   Toxicity to reproduction

A high systemic concentration of manganese may cause reproductive and developmental effects as evidenced by degenerative changes in testes of male animals injected, instilled or gavaged with manganese and by embryo-lethality, postimplantation loss, and structural abnormalities and delays in pups in studies where manganese was injected during gestation at doses from about 1 mg Mn/kg b.w. per day or gavaged at doses from about 33 mg Mn/kg b.w. per day.

Studies in mice and rats with oral intake of manganese indicate that ingestion at doses from about 1050 mg Mn/kg b.w. per day can lead to delayed maturation of the reproductive function in male offspring probably due to decreased testosterone secretion by Leydig cells. However, sperm count and fertility did not appear to be affected at manganese doses as high as 1050 mg Mn/kg b.w. per day. A diet low in iron worsened the reproductive effects.

No female reproductive effects were found in rats fed manganese sulphate in their diet at doses up to 187 mg Mn/kg b.w. per day (highest dose tested) for 8 weeks prior to mating and until gestational day 21 or in pregnant rats ingesting other inorganic manganese substances at even higher doses.No gross malformations were observed in the foetuses of the rats fed manganese sulphate in their diet at doses up to 187 mg Mn/kg b.w. per day (highest dose tested) for 8 weeks prior to mating and until gestational day 21. The highest dose did cause a significant increase in foetal manganese and a decrease in foetal iron content.

In most studies, no biochemical or behavioural signs of neurotoxicity were evident in pups. Male pups exposed in utero and postnatally via drinking water to the dams with 620 mg Mn/kg b.w. per day, did not perform different than control rats in a number of behavioural tests that measured spontaneous motor activity, memory, and cognitive ability, and did not have any neurochemical alterations. In neonatal rats dosed with 22 mg Mn/kg b.w. per day with a micropipette for the first 21 days of their life, the dopamine level was increased and a significant increase in amplitude of the auditory startle reflex was induced. A decreased dopamine level and changes in the level of enzymes involved in the synthesis or metabolism of the neurotransmitter have been observed after postnatal dosing but mainly in the gavage studies at doses from about 1 mg Mn/kg b.w. per day.

In utero exposure to manganese did not alter gross locomotor activity, different behavioural parameters and learning performance in mice pups whose mothers had been exposed to manganese at an average concentration of 61 mg Mn/m³ 7 hours/day, 5 days/week for 16 weeks prior to conception and to either filtered air or manganese during the gestation period. The only effect observed was a reduced weight in pups of mothers exposed to manganese before conception and filtered air after conception.

6.4.4   Mutagenic and genotoxic effects

In vitro, manganese sulphate was negative in one Ames test with 5 strains of Salmonella typhimurium with or without metabolic activation. It was positive in another Ames test with strain TA97 without metabolic activation, in a fungal gene conversion/reverse mutation assay, in the sister chromatid exchange test in CHO cells with and without metabolic activation, and in a test for chromosomal aberrations in CHO cells without metabolic activation.

In vivo assays in mice showed that oral doses of manganese sulphate caused an increased incidence of micronuclei and chromosomal aberrations in bone marrow. Manganese sulphate was negative for sex-linked recessive lethal mutations in male germ cells in fruit flies.

6.4.5   Carcinogenic effects

Exposure to high oral doses of manganese sulphate for 2 years may cause small increases in thyroid gland follicular cell adenomas (in mice at 731 mg Mn/kg b.w. per day), pituitary adenomas (in female mice at 905 mg Mn/kg b.w. per day), and pancreatic adenomas and carcinomas (in male rats at all doses up to 331 mg Mn/kg b.w. per day). However, rats and mice exposed to about 230 mg Mn/kg b.w. per day for 2 years showed no increases in tumour incidence in one of the studies.

Manganese is an essential element in the nutrition of humans and animals. The concentration of manganese in our body following oral exposure is normally wellregulated. However, the homeostatic system may become overloaded which may result in adverse effects. Most of the observed adverse effects following exposure to manganese have been observed in workers exposed by inhalation.

Neurotoxicity following inhalation is the critical effect of manganese. Clear evidence exist from studies of human workers that inhalation exposure to manganese for longer periods can lead to serious neurological effects (resembling parkinsonism) that in most cases are irreversible. These effects may occur at concentrations of manganese in respirable dust in the range of 0.027 to 0.215 mg Mn/m³ and in total dust in the range of 0.14 to 1.59 mg Mn/m³. Studies in rats indicate that manganese may be distributed directly to the brain from the nasal cavity via the olfactory pathway, which may in part explain why it is mainly neurological effects that are seen after inhalation exposure. In addition, one study in monkeys that had been exposed to an aerosol of manganese chloride showed that most manganese was excreted fairly quickly but a portion of the manganese was retained in the lungs and brain and was cleared with a longer half-life.
Other effects observed in workers exposed to manganese by inhalation included an elevated serum prolactin and cortisol level, a lowered blood pressure, and inflamed lungs (also seen in rodents). The different systemic effects seen in rodents exposed orally to manganese occurred at relatively high concentrations.
Monkeys exposed to manganese exhibit neurological symptoms resembling those observed in workers exposed to manganese but in rodents this is seldom the case. For this reason, studies in rodents may not necessarily be relevant models for the toxicity of manganese in humans even though neurochemical changes are sometimes revealed in rodents exposed to manganese.

Only limited evidence exist that oral exposure to excess manganese in humans lead to neurological effects similar to those reported for inhalation exposure.

Manganese has the potential to cause reproductive and developmental effects as evidenced by reproductive effects seen in workers exposed to manganese by inhalation and by reproductive and developmental effects seen in rodent studies. However, most of the reproductive and developmental effects seen in rodent studies occurred after exposure via gavage or injection where a high systemic concentration of manganese would be found. In most studies, no biochemical or behavioural signs of neurotoxicity were evident in pups even though the absorption and/or retention of manganese are known to be higher in neonates. However, the dopamine level and the amplitude of the auditory startle reflex was increased in neonatal rats dosed with 22 mg Mn/kg b.w. per day with a micropipette for the first 21 days of their life. A reduced weight of pups of mothers exposed to 61 mg Mn/m³ for 16 weeks before conception was the only effect observed in these pups.

It is a cause of concern that manganese was positive in several in vitro and in vivo genotoxic assays. Small increases in thyroid gland follicular cell adenomas, pituitary adenomas, and pancreatic adenomas and carcinomas did occur in rodents exposed orally to relatively high doses of manganese for 2 years.

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