dialuminium manganese tetraoxide, spinel type

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

other: Expert statement on the interpretation of the bioaccessibility test data obtained from the study DIN 19738 (Soil quality - Bioaccessibility of organic and inorganic pollutants from contaminated soil material)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: expert statement

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Objective of study:

absorption

Qualifier:

according to guideline

Guideline:

other: expert statement

Deviations:

not applicable

GLP compliance:

no

Remarks:

not applicable

Type:

absorption

Results:

Based on a mobilised mass of 6901.91 µg/g (sample 3, which was considered an outlier in the study report), Manganese bioaccessibility in a very worst-case would result in 2.1 %.

Type:

absorption

Results:

Based on the mean concentration of 50.9 mg/L in four samples, the Aluminum bioaccessibility in a very worst-case would result in 0.02 %.

Bioaccessibility (or Bioavailability) testing results:

Based on a mobilised mass of 6901.91 µg/g (sample 3, which was considered an outlier in the study report), Manganese bioaccessibility results in 2.1 %. This value is very close to the absorption of Manganese from the gastrointestinal tract of 3 – 5 % reported in the literature for soluble Manganese compounds (ATSDR, 2012, SCOEL, 2011): “The amount of manganese absorbed across the gastrointestinal tract in humans is variable, but typically averages about 3–5 %” (SCOEL, 2011). “The absorption is expected to be higher for soluble forms of manganese compared with relatively insoluble forms of manganese” (ATSDR, 2012). Since the registered substance Galaxite is an insoluble compound, Manganese bioaccessibility is expected to be up to one order of magnitude lower than 2.1 %.

With regard to the calculated Aluminum bioaccessibility based on the limit of detection, there is an issue due to adsorption of Aluminum ions onto the particles surface of the test item. Since this is the same property for the registered substance Galaxite as well, a more or less similar situation is expected in the stomach also. Thus, it is reasonable to assume, that a “true” concentration of mobilized masses that could be systemically available is that, which is actually measured in the samples with the test item. The registrant realizes that this approach is not according to the current DIN guideline and the amounts of Aluminum found in the blanks should be subtracted, but this seems to be the most plausible explanation allowing to calculate a bioaccessibility value based on very worst-case results. Based on the mean concentration of 50.9 mg/L in four samples, the Aluminum bioaccessibility results in 0.02 %. Tentatively, this value is plausible for such an insoluble Aluminum containing compound like the registered substance Galaxite, since the reported absorption values from drinking water and diets are several times higher than this value, which might then come close to a “true” value: “Approximately 0.1–0.6% of ingested aluminum is usually absorbed, although absorption of less bioavailable forms, such as aluminum hydroxide, can be on the order of 0.1%. The unabsorbed aluminum is excreted in the feces” (ATSDR, 2008). Aluminum absorption from drinking water is reported to be 0.07 - 0.39 % in humans and 0.04 - 0.06 % in rats (ATSDR, 2008). Aluminum absorption of a number of poor soluble compounds from diets is reported to be in the range of 0.27 - 0.60 % and to be similar in animals and humans: “The oral absorption of aluminum can vary 10-fold based on chemical form” (ATSDR, 2008).

Conclusions:

Based on comparison of newly calculated bioaccessibility values via GI tract, even though facilitating the obviously not very accurate bioaccessibility study results, do support the criterion “there is no evidence of absorption” and could serve as an additional piece for the weight of evidence approach. In case the bioaccessibility study in gastrointestinal fluid is going to be repeated, the registrant still believes that the newly obtained results on bioaccessibility may not deviate significantly from the results obtained in this study.

Executive summary:

Based on a mobilised mass of 6901.91 µg/g (sample 3, which was considered an outlier in the study report), Manganese bioaccessibility results in 2.1 %. This value is very close to the absorption of Manganese from the gastrointestinal tract of 3 – 5 % reported in the literature for soluble Manganese compounds (ATSDR, 2012, SCOEL, 2011):“The amount of manganese absorbed across the gastrointestinal tract in humans is variable, but typically averages about 3–5 %”(SCOEL, 2011).“The absorption is expected to be higher for soluble forms of manganese compared with relatively insoluble forms of manganese”(ATSDR, 2012). Since the registered substance Galaxite is an insoluble compound, Manganese bioaccessibility is expected to be up to one order of magnitude lower than 2.1 %.

With regard to the calculated Aluminum bioaccessibility based on the limit of detection, there is an issue due to adsorption of Aluminum ions onto the particles surface of the test item. Since this is the same property for the registered substance Galaxite as well, a more or less similar situation is expected in the stomach also. Thus, it is reasonable to assume, that a “true” concentration of mobilized masses that could be systemically available is that, which is actually measured in the samples with the test item. The registrant realizes that this approach is not according to the current DIN guideline and the amounts of Aluminum found in the blanks should be subtracted, but this seems to be the most plausible explanation allowing to calculate a bioaccessibility value based on very worst-case results. Based on the mean concentration of 50.9 mg/L in four samples, the Aluminum bioaccessibility results in 0.02 %. Tentatively, this value is plausible for such an insoluble Aluminum containing compound like the registered substance Galaxite, since the reported absorption values from drinking water and diets are several times higher than this value, which might then come close to a “true” value:“Approximately 0.1–0.6% of ingested aluminum is usually absorbed, although absorption of less bioavailable forms, such as aluminum hydroxide, can be on the order of 0.1%. The unabsorbed aluminum is excreted in the feces”(ATSDR, 2008). Aluminum absorption from drinking water is reported to be 0.07 - 0.39 % in humans and 0.04 - 0.06 % in rats (ATSDR, 2008). Aluminum absorption of a number of poor soluble compounds from diets is reported to be in the range of 0.27 - 0.60 % and to be similar in animals and humans:“The oral absorption of aluminum can vary 10-fold based on chemical form”(ATSDR, 2008).

The registrant believes that the above described comparisons, even though facilitating the obviously not very accuratebioaccessibility study results, do support the criterion“there is no evidence of absorption”and could serve as an additional piece for the weight of evidence approach. In case the bioaccessibility study in gastrointestinal fluid is going to be repeated, the registrant still believes that the newly obtained results on bioaccessibility may not deviate significantly from the results obtained in this study.

Reference 2

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

other: Assesment of theoretical uptake of Galaxite by inhalation based on bioaccessibility measurements in the lung artificial fluid.

Adequacy of study:

weight of evidence

Study period:

2018

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: expert statement

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Objective of study:

absorption

Qualifier:

according to guideline

Guideline:

other: expert statement

Deviations:

not applicable

GLP compliance:

no

Remarks:

not applicable

Type:

absorption

Results:

The bioavailability of the metal-ions is proven to be extremely low, i.e. the potential uptake of Aluminium and Manganese from the registered substance would result in levels 450 and 250 times lower than the normal serum concentration, respectively

Type:

absorption

Results:

Body burden at levels of 1/450th and 1/250th of the normal serum levels (of Aluminum and Manganese respectively) will not result in toxicological effects since normal serum fluctuations will be of the same order of magnitude

Bioaccessibility (or Bioavailability) testing results:

The uptake by inhalation would lead to body burdens of Aluminum and Manganese in the range far below of the normal serum levels as indicated by the following calculation:
•          determined bioavailability of Aluminum for Galaxite in the lung is 1.01 x 10-2%
•          determined bioavailability of Manganese for Galaxite in the lung is 5.71 x 10-3%.
•          respiratory volume of ca. 10 m³ per worker’s shift
•          blood volume of ca. 5 L (as a worst-case assumption)
•          occupational exposure limit (OEL-TWA) of 10 mg/m³ for total (inert) dust (TRGS 900: Technical Guidance for dangerous substances: Airborne exposure limits, highest value as a worst-case assumption).
Based on these calculations, the mass of Aluminum that could be solubilised in the lung would account for 2.02 μg/L blood. The normal serum concentration of Aluminum (background value) of the average adult is 1 to 2 μg/L. However, this theoretical approach is representative for a 100 % inhalable fraction but does not take into account the practically relevant particle size distribution.
For Galaxite, only 0.1 % of the particles are < 67 µm and thus respirable. Thus, the mass of Aluminum that could realistically be solubilized would account for 0.00202 µg/L blood, i.e., very
roughly the potential additional “burden” is at least a factor of 450 less than normal serum (background) levels.
The mass of Manganese that could be solubilised in the lung would account for 0.0011 μg/L blood. The normal serum concentration of Manganese of the average adult is 0.3 to 1.1 μg/L, i.e. the potential additional “burden” is a factor of 250 less than normal serum (background) levels.

Conclusions:

The bioavailability of the metal-ions is proven to be extremely low, i.e. the potential uptake of Aluminium and Manganese from the registered substance would result in levels 450 and 250 times lower than the normal serum concentration, respectively,” and
- "Body burden at levels of 1/450th and 1/250th of the normal serum levels (of Aluminum and Manganese respectively) will not result in toxicological effects since normal serum fluctuations will be of the same order of magnitude."

Executive summary:

The registrant re-evaluated the available bioaccessibility study results on Galaxite and concluded that the derived conclusions, i.e. following two prerequisites, should be amended:

-"The bioavailability of the metal-ions is proven to be extremely low, i.e. the potential uptake of aluminum and manganese from the registered substance would result in levels 40 and 25 times lower than the normal serum concentration, respectively,” and

- "Body burden at levels of 1/25th or 1/40th of the normal serum levels (of aluminum and manganese) will not result in toxicological effects (normal serum fluctuations will be of the same order of magnitude)."

 

Although inhalation is not a relevant route of exposure for the registered substance Galaxite, the registrant recalculated theoretical uptake by inhalation based on bioaccessibility measurements in the lung artificial fluid. This is because of the adapted bioaccessibility values for Aluminum and Manganese.

The uptake by inhalation would lead to body burdens of Aluminum and Manganese in the range far below of the normal serum levels as indicated by the following calculation:

•          determined bioavailability of Aluminum for Galaxite in the lung is 1.01 x 10^-2%

•          determined bioavailability of Manganese for Galaxite in the lung is 5.71 x 10^-3%.

•          respiratory volume of ca. 10 m³ per worker’s shift

•          blood volume of ca. 5 L (as a worst-case assumption)

•          occupational exposure limit (OEL-TWA) of 10 mg/m³ for total (inert) dust (TRGS 900: Technical Guidance for dangerous substances: Airborne exposure limits, highest value as a worst-case assumption).

Based on these calculations, the mass of Aluminum that could be solubilised in the lung would account for 2.02 μg/L blood. The normal serum concentration of Aluminum (background value) of the average adult is 1 to 2 μg/L. However, this theoretical approach is representative for a 100 % inhalable fraction but does not take into account the practically relevant particle size distribution.

For Galaxite, only 0.1 % of the particles are < 67 µm and thus respirable. Thus, the mass of Aluminum that could realistically be solubilized would account for 0.00202 µg/L blood, i.e., very

roughly the potential additional “burden” is at least a factor of 450 less than normal serum (background) levels.

The mass of Manganese that could be solubilised in the lung would account for 0.0011 μg/L blood. The normal serum concentration of Manganese of the average adult is 0.3 to 1.1 μg/L, i.e. the potential additional “burden” is a factor of 250 less than normal serum (background) levels.

 

For comparison, respirable Indicative Occupational Exposure Limit Value (IOELV) of 0.05 mg Mn/m³ and an inhalable IOELV of 0.2 mg Mn/m³ are recommended and neither respiratory nor cardiovascular toxicity would be expected at inhalable exposures of 1 mg Mn/m³ or less (SCOEL, 2011).

Inhalation Minimal Risk Levels (MRLs) for Aluminum based on respiratory effects were not derived, but an MRL of 1 mg Al/kg body weight per day has been derived for intermediate-duration oral exposure (15 – 364 days) to Aluminum.

 

In conclusion, the above cited two prerequisites should be therefore amended as follows:

-"The bioavailability of the metal-ions is proven to be extremely low, i.e. the potential uptake of Aluminium and Manganese from the registered substance would result in levels 450 and 250 times lower than the normal serum concentration, respectively,” and

- "Body burden at levels of 1/450th and 1/250th of the normal serum levels (of Aluminum and Manganese respectively) will not result in toxicological effects since normal serum fluctuations will be of the same order of magnitude."

Description of key information

Oral absorption

Bioaccessibility of Manganese from Galaxite was tested in a study with synthetic gastrointestinal fluids. The study result does not allow a definitive quantification regarding the bioavailability of the registered substance fro the GI tract because of 1) a large difference between the duplicate measurements of milk powder supplemented samples, 2) the fact, that the outlier data was not applied on the less concentrated sample (please see Registrabt's comments on ECHA draft decision attached under section 13). Nevertheless, the registrant is of the opinion, that the data gained from this test does allow for a tentative evaluation and therefore re-evaluated the currently available bioaccessibility study results for Manganese using the highest values as a worst-case situation for mobilized masses of the test item even though they may not be very precise. Therewith, the registrant intends to provide at least some kind of controversial discussion on the interpretation of the bioaccessibility test data showing their basic plausibility which does indeed allow for some tentative conclusions.

Based on a mobilised mass of 6901.91 µg/g (sample 3, which was considered an outlier in the study report), Manganese bioaccessibility results in 2.1 %. This value is very close to the absorption of Manganese from the gastrointestinal tract of 3 – 5 % reported in the literature for soluble Manganese compounds (ATSDR, 2012, SCOEL, 2011):“The amount of manganese absorbed across the gastrointestinal tract in humans is variable, but typically averages about 3–5 %”(SCOEL, 2011).“The absorption is expected to be higher for soluble forms of manganese compared with relatively insoluble forms of manganese”(ATSDR, 2012). Since the registered substance Galaxite is an insoluble compound, Manganese bioaccessibility is expected to be up to one order of magnitude lower than 2.1 %.

Absorption by inhalation

Bioaccessibility of Manganese from Galaxite was tested in a study with the lung artificial fluid.

The uptake by inhalation would lead to body burdens of Manganese in the range far below of the normal serum levels as indicated by the following calculation:

•          determined bioavailability of Manganese for Galaxite in the lung is 5.71 x 10^-3%.

•          respiratory volume of ca. 10 m³ per worker’s shift

•          blood volume of ca. 5 L (as a worst-case assumption)

•          occupational exposure limit (OEL-TWA) of 10 mg/m³ for total (inert) dust (TRGS 900: Technical Guidance for dangerous substances: Airborne exposure limits, highest value as a worst-case assumption).

Based on these parameters, the mass of Manganese that could be solubilised in the lung would account for 0.0011 μg/L blood. The normal serum concentration of Manganese of the average adult is 0.3 to 1.1 μg/L, i.e. the potential additional “burden” is a factor of 250 less than normal serum (background) levels.

 

For comparison, respirable Indicative Occupational Exposure Limit Value (IOELV) of 0.05 mg Mn/m³ and an inhalable IOELV of 0.2 mg Mn/m³ are recommended and neither respiratory nor cardiovascular toxicity would be expected at inhalable exposures of 1 mg Mn/m³ or less (SCOEL, 2011).

Dermal absorption

In case, if certain amounts of manganese are released from Galaxite in the moisture of skin, only negligible amounts of manganese will be available for systemic absorption. Studies regarding the absorption of manganese through the skin are very limited. No studies on acute dermal hazard are available for manganese cation (ATSDR 2012).

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

2.1

Absorption rate - inhalation (%):

0.006

Additional information

Toxicokinetic of Manganese is outlined in the attached document.