dialuminium manganese tetraoxide, spinel type

Additional toxicological data

Administrative data

Endpoint:

additional toxicological information

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2009-05-05 - 2009-11-05

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP-study

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

data waiving: supporting information

Reference

Endpoint:

sub-chronic toxicity: oral

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Justification for type of information:

JUSTIFICATION FOR DATA WAIVING
As outlined in the current ECHA draft decision (from 07/05/2018) (please see attached under section 13) on the updated registration dossier to ECHA´s follow-up evaluation, “the request in the original decision was not met, and you are still required to provide Sub-chronic toxicity study (90-day), oral route (Annex IX, Section 8.6.2.) as requested in the original decision”.

Referring to the waiving arguments inserted in the section above, the Registrant commenting ECHA draft decision from 07 May 2018 regarding the endpoint on sub-chronic toxicity study (90-day) revised several existing pieces of evidence and added new pieces of evidence to justify waiving of the information requirements:
The registrant agrees that test data on the requested 90-day study is not available in the current registration dossier. However, the registrant is still intending to cover this toxicological endpoint providing an appropriate adaptation based on Annex XI, Section 1.2 (Weight of evidence).

The registrant concludes, that no additional and separate testing for repeated dose toxicity is necessary, as there is sufficient experimental evidence on low intrinsic toxic potency of the registered substance and its structural analogues of Spinel type minerals. As described already in the field "Data waiving" and as outlined in the waiving arguments in the section 7.5.2. "Waiving_Repeated dose toxicity (90-day study): inhalation " (please see cross-reference), the substance meets criteria of a substance being “unreactive, insoluble and not inhalable and there is no evidence of absorption and no evidence of toxicity in a 28-day ‘limit test’ particularly if such a pattern is coupled with limited human exposure”, according to REACH Regulation Annex IX, 8.6.2, Column 2.
Above prerequisite elements covering Annex IX, 8.6.2, Column 2 requirements have been discussed in the section 7.5.2 "Waiving_Repeated dose toxicity (90-day study): inhalation" following by Nos 1 through 4 and brought together for amalgamation into the weight of evidence approach as of Annex XI, Section 1.2.
Please refer also to an asessment of absorption potential of Aluminum and Manganesium from Galaxite, based on newly calculated bioaccessibility values (new piece of evidence; section 7.1) and to an assessment of a hypothetical case that an oral study would have been conducted with the registered substance Galaxite (section 7.5.1.; please see cross-references).

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

Critical effects observed:

not specified

Cross-reference 2

Reason / purpose for cross-reference:

assessment report

Reference

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.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2009

Report date:

2009

Materials and methods

Type of study / information:

Determination of the resorption in the digestive tract of Galaxite according to DIN 19738 to determine the bioavailable parts.

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

other: DIn 19738

Deviations:

yes

Remarks:

The composition of the test item was not determined, but calculated from information provided by the sponsor. Temperature in some conducts was outside the range of 37 ± 1 °C. The sediment was not leached with deionised H2O after centrifugation.

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: DIN 19738

Deviations:

yes

Remarks:

The samples were stored in closed vessels at 2 - 8°C. pH was not measured after the first 30 minutes.The solutions were centrifuged at 2000 g, instead at 7000 g. The test item is a powder and was used without preparation.

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

1302-69-8

Cas Number:

1302-69-8

IUPAC Name:

1302-69-8

Constituent 2

Reference substance name:

tetraoxo dialuminium manganese

IUPAC Name:

tetraoxo dialuminium manganese

Results and discussion

Any other information on results incl. tables

Analytical Determinations of Al

The following table gives the measured values of Al, which was measured after thermal decomposition and resolution in HCl via AAS in a C₂H₂/N₂O-flame.

Measured values for Al in solutions, in mg/L

Sample	1	2	3	4	Blank 1	Blank 2
measured value for Al	0.460	0.198	0.737	0.573	1.287	1.346
dilution factor	100	100	100	100	100	100
concentration in original test solution	46.0	19.8	73.7	57.3	128.7	134.6

As all values lay below the values which were measured in the blanks, Al can not be used to determine bio-accessibility of the test item.

 Analytical Determinations of Mn

The next table gives the measured values of Mn, which was measured after thermal decomposition and resolution in HCl via AAS in a C₂H₂/air-flame.

Measured values for Mn in solutions, in mg/L

Sample	1	2	3	4	Blank 1	Blank 2
measured value forMn	1.01	1.06	1.38	0.37	< LOQ	< LOQ
dilution factor	5	5	50	50	10	10
concentration in original test solution	5.06	5.30	69.0	18.6	< LOQ	< LOQ

 Calculation of Mobilised Mass

The mobilised masses of the elements were calculated as

 

w_i,mob  = (C_i   * V)/m_E  

with

 

w_i,mob                                     = mobilised part in µg/g test item per element

C_i                                           = measured element concentration in µg/L

V                                            = total volume in L of the aqueous phase (standard is 200 ml)

m_E                                         = weight of used test item (standard is 2.0 g)

 

Calculation of Bioaccessibility

Bioaccessibility will be calculated as

 

R_i  = (w_i,mob * 100%)/   w_i,fest  

with

 

R_i                                           = bioaccessible part in %

w_i,mob                                     = mobilised part in µg/g test item per element

w_i,fest                                      = part of the element in the test item in µg/g

 

Results

As the concentrations of the measured element (Al) in the blanks are mostly higher than in the samples, calculation of effective concentrations was not reasonable. The measurements of Mn showed minor valuesin the digestive tract.

mobilised masses, bioaccessibility of Mn (Samples without addition of milk powder)

Sample	1	2	Mean	sd	RSD
mobilised masses of test item in µg/g	505.90	530.02	517.96	17.05	3.29%
bioaccessibility in %	1.54E-03	1.61E-03	1.58E-03	5.19E-05	3.29%

mobilised masses, bioaccessibility of Mn (Samples with addition of milk powder)

Sample	3*	4
mobilised masses of test item in µg/g	6901.91	1857.14
bioaccessibility in %	2.10E-02	5.66E-03

For the sample 3 Grubbs’s outlier test was applied: The suspect Grubbs’s value G_suspectfor w_i,(mob)= 6901.91 µg/g is 1.467 and the critical Grubbs’s value G_criticalis 1.463. As G_suspect> G_criticalfor this value, sample 3 was stated as outlier.

 

From the LOQ of Al (250 µg/L) a maximum bioaccessibility was calculated.

mobilised masses and bioaccessibility of Al

Parameter	Calculated from LOQ (Al)
Mobilised mass of test item in µg/g	25
Bioaccessibility in %	< 9.70 * 10^-5

Applicant's summary and conclusion

Conclusions:

All measurements of Al show values lying lower than in the blanks. The measurements of Mn show minor resorption in the digestive tract. Sample 3 (Mn-content) showed great deviations from the other 3 samples and the value was therefore stated as outlier (Grubbs’s outlier test).
This difference between Al and Mn can occur maybe because of adsorption of Al and Mn ions in the solution on the surface of the test item.

Executive summary:

Two tests with and two tests without the addition of full milk powder have been performed, as well as two blanks with and without milk powder.

A part of the remaining solutions then was thermically digested and re-dissolved in conc. HCl and water. The resulting solutions were measured via AAS for Mn and Al.

All Al determinations were below LOQ, therefore only Mn was used for the calculation of the bioaccessibilities.

The Manganese bioaccessibility for sample 3 (with milk powder supplemented sample) is 0.57 % and for Aluminum bioaccessibility 9.7 x 10^-3% based on the limit of quantification of the analytical method.