Reaction mass of disodium [2,2'-(imino-kappaN)dibutanedioato-kappa2O1,O4(4-)]manganese(2-) and sodium sulphate

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

repeated dose toxicity: inhalation

Remarks:

other: sub-acute, sub-chronic and chronic study results

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The Agency for Toxic Substances and Disease Registry (ATSDR) is peer-reviewed toxicological profile that reviews the key literature and describes a hazardous substance's toxicologic properties.

Data source

Reference

Reference Type:

review article or handbook

Title:

Toxicological profile for manganese.

Author:

ATSDR

Year:

2012

Bibliographic source:

U.S. Department of Health and Human Services. Public Health Service Agency for Toxic Substances and Disease Registry. September, 2012

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: guidelines developed by ATSDR and EPA (published in the Federal Register on April 17, 1987).

Deviations:

not applicable

Principles of method if other than guideline:

The ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects information for manganese.

GLP compliance:

no

Remarks:

not applicable (it is a review)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Manganese

EC Number:

231-105-1

EC Name:

Manganese

Cas Number:

7439-96-5

IUPAC Name:

manganese(2+)

Details on test material:

- Name of test material (as cited in study report): manganese.

Manganese is a naturally occurring substance found in many types of rocks and soil. Pure manganese is a silver-colored metal; however, it does not occur in the environment as a pure metal. Rather, it occurs combined with other substances such as oxygen, sulfur, and chlorine. Manganese is a trace element and is necessary for good health.

Test animals

Species:

other: animals and humans

Administration / exposure

Route of administration:

inhalation: dust

Results and discussion

Effect levels

1

Dose descriptor:

conc. level: Minimal Risk Level (MRL)

Effect level:

0 mg/m³ air

Based on:

element

Remarks:

manganese

Sex:

male/female

Basis for effect level:

other: based on human data (including uncertainties factors covering neonates, children, pregnant women, age and stage of health).

2

Dose descriptor:

conc. level: TWA

Effect level:

5 mg/m³ air

Based on:

other: compounds and fumes

Sex:

male/female

Basis for effect level:

other: OSHA set a legal limit of 5 mg/m3 for manganese compounds and fumes in air averaged over an 8-hour work day (for general industry; established in 2007).

3

Dose descriptor:

conc. level: TWA

Effect level:

0.2 mg/m³ air

Based on:

element

Remarks:

manganese

Sex:

male/female

Basis for effect level:

other: TLV (8-hour TWA) set by ACGIH (2008)

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

The general population is exposed to manganese through consumption of food and water, inhalation of air, and dermal contact with air, water, soil, and consumer products that contain manganese. The primary source of manganese intake is through diet. Although low levels of manganese intake are necessary for human health, exposures to high manganese levels are toxic. Reports of adverse effects resulting from manganese exposure in humans are associated primarily with inhalation in occupational settings. Inhaled manganese is often transported directly to the brain before it is metabolized by the liver. The symptoms of manganese toxicity may appear slowly over months and years. Manganese toxicity can result in a permanent neurological disorder known as manganism with symptoms that include tremors, difficulty walking, and facial muscle spasms. These symptoms are often preceded by other lesser symptoms, including irritability, aggressiveness, and hallucinations. Some studies suggest that manganese inhalation can also result in adverse cognitive effects, including difficulty with concentration and memory problems. Although the workplace is the most common source of excess inhalation of manganese, frequent inhalation of fumes from welding activities in the home can produce a risk of excess manganese exposure leading to neurological symptoms. Environmental exposures to airborne manganese have been associated with similar preclinical neurological effects and mood effects as are seen in occupational studies. Acute or intermediate exposure to excess manganese also affects the respiratory system. 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.

The critical targets of manganese toxicity are the nervous system, respiratory system, reproductive system (section 7.8.1), and development (section 7.8.2.).

Neurological Effects.

There is clear evidence from studies of humans exposed to manganese dusts in mines and factories that inhalation of high levels of manganese can lead to a series of serious and ultimately disabling neurological effects in humans. This disease, termed manganism, typically begins with feelings of weakness and lethargy. As the disease progresses, a number of other neurological signs may become manifest. Although not all individuals develop identical signs, the most common are a slow and clumsy gait, speech disturbances, a masklike face, and tremors. The neurological symptoms may improve when exposure ceases; however, in most cases, the symptoms are found to persist for many years post-exposure. In addition, a syndrome of psychological disturbances (hallucination, psychosis) frequently emerges, although such symptoms are sometimes absent. As the disease progresses, patients develop severe muscle tension and rigidity and may be completely and permanently disabled. Workplace inhalation exposure levels producing overt symptoms of manganism have been on the order of 2–22 mg manganese/m3. While manganese neurotoxicity has clinical similarities to Parkinson’s disease, it can be clinically distinguished from Parkinson’s. Manganism patients present a hypokinesia and tremor that is different from Parkinson’s patients. In addition, manganism patients sometimes have psychiatric disturbances early in the disease, a propensity to fall backward when pushed, less frequent resting tremor, more frequent dystonia, a “cock-walk”, and a failure to respond to dopaminomimetics.

Subclinical neurological effects have been observed in numerous studies of workers exposed to manganese dusts at lower exposure levels than those associated with symptoms of overt manganism. These effects include decreased performance on neurobehavioral tests; significantly poorer eye-hand coordination, hand steadiness, and reaction time; poorer postural stability; and lower levels of cognitive flexibility. Manganese air concentrations producing these effects in chronically exposed workers range from about 0.07 to 0.97 mg manganese/m3.

Studies in communities surrounding manganese industries have also reported associations between manganese exposure and subclinical neurological effects in adults and children. In a study of men and women living close to a manganese alloy production plant, a blood manganese level-age interaction was observed, with the poorest performance on neurological tests occurring among those >50 years old who had the highest blood manganese levels. Additional studies of environmentally exposed adults reported attention impairments, poorer postural stability, and subclinical motor impairments at environmental air exposures >0.1 μg manganese/m3; however, other potential sources of environmental exposure were not accounted for. In several studies of children, associations have been reported between manganese concentrations in blood or hair and motor impairment and deficits in neurodevelopment and intellectual functions.

Respiratory Effects.

Inhalation exposure to manganese dusts often leads to an inflammatory response in the lungs of both humans and animals. This generally leads to an increased incidence of cough and bronchitis and can lead to mild-to-moderate injury of lung tissue along with minor decreases in lung function. In addition, susceptibility to infectious lung disease may be increased, leading to increased pneumonitis and pneumonia in some manganese-exposed worker populations. These effects have been reported primarily in workers exposed to fairly high concentrations of manganese dusts in the workplace, although there are some data that indicate that, in populations living and attending school near ferromanganese factories, there was an increased prevalence of respiratory effects. The risk of lung injury in people exposed to the levels of manganese typically found in the general environment is expected to be quite low. However, exposure to manganese-containing dusts from factories, mining operations, automobile exhaust, or other sources may be of concern. It should be noted that these effects on the lung are not unique to manganese-containing dusts but are produced by a variety of inhalable particulate matter.

Applicant's summary and conclusion

Conclusions:

An MRL of 0.0003 mg manganese/m3 (manganese in respirable dust; 0.3 μg manganese/m3) has been derived for chronic inhalation exposure (365 days or more) to manganese (all human sub-populations are covered). For workers, there exist TWA of 5 mg/m³ (OSHA, 2007) for manganese compounds and dusts and TWA of 0.2 mg/m³ for elemnet manganese (ACGIH, 2008).

Executive summary:

Manganese is an essential nutrient, and eating a small amount of it each day is important to stay healthy.

The most common health problems in workers exposed to high levels of manganese involve the nervous system. These health effects include behavioral changes and other nervous system effects, which include movements that may become slow and clumsy. This combination of symptoms when sufficiently severe is referred to as “manganism.” Other less severe nervous system effects such as slowed hand movements have been observed in some workers exposed to lower concentrations in the work place. The inhalation of a large quantity of dust or fumes containing manganese may cause irritation of the lungs which could lead to pneumonia. Loss of sex drive and sperm damage has also been observed in men exposed to high levels of manganese in workplace air. The manganese concentrations that cause effects such as slowed hand movements in some workers are approximately twenty thousand times higher than the concentrations normally found in the environment. Manganism has been found in some workers exposed to manganese concentrations about a million times higher than normal air concentrations of manganese.

An MRL of 0.0003 mg manganese/m3 (manganese in respirable dust; 0.3 μg manganese/m3) has been derived for chronic inhalation exposure (365 days or more) to manganese. This value includs uncertainties factors covering neonates, children, pregnant women, age and stage of health. For workers, OSHA set a legal limit of 5 mg/m3 for manganese compounds and dust in air averaged over an 8-hour work day. A concentration limit of 0.2 mg/m³ as 8 -hour TWA was set by ACGIH for manganese (element).