dialuminium manganese tetraoxide, spinel type

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

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 Pre-natal developmental toxicity study (Annex IX, Section 8.7.2.) in rats or rabbits, oral route as requested in the original decision”.

Referring to the waiving arguments inserted in the section above, the Registrant commented ECHA draft decision from 07 May 2018 regarding the endpoint on prenatal developmental toxicity study and 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 prenatal developmental (PND) toxicity 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).
According to REACH regulation, column 2, section 8.7, of Annex IX, the study does not need to be conducted if "the substance is of low toxicological activity (no evidence of toxicity seen in any of the tests available), it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure (e.g. plasma/blood concentrations below detection limit using a sensitive method and absence of the substance and of metabolites of the substance in urine, bile or exhaled air) and there is no or no significant human exposure" .
The registrant concludes, that no additional and separate testing for prenatal developmental 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. The special provisions outlined in the column 2, section 8.7, of Annex IX are in principle met. This was described already above in the original waiver in the field "Data waiving" and outlined in sufficient detals in the additional 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” 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 two assessments of a hypothetical case that an oral and an inhalation studies would have been conducted with the registered substance Galaxite (additional piece of evidence; section 7.5.1.; please see cross-references).

Additionally, the newly calculated bioaccessibility values based on some worst-case assumptions, can be used likewise for comparison with the reported developmental toxicity levels of Aluminum and Manganese in animal studies. Similarly, as is the case for the 90-day study, if a PND study with the registered substance were conducted and the limit dose of 1000 mg/kg body weight was used, and considering the re-calculated bioaccessibility values of 2.1 % and 0.02 %, the bioavailable doses would be 6.9 and 0.06 mg/kg body weight per day for Manganese and Aluminum, respectively. These dose levels are far below effect levels, LOAELs and NOAELs established for numerous Manganese and Aluminum compounds in animal developmental studies.
For Manganese compounds tested in developmental studies of different durations and designs and in different species, NOAEL values were reported to be in the range of 11 – 624 mg Mn/kg body weight per day (ATSDR, 2012). Manganese ingestion led to delayed maturation of the reproductive system in males only at very high doses (> 1300 mg Mn/kg body weight per day). For Aluminum compounds tested in developmental studies of intermediate exposure durations NOAEL values were in the range of 26 - 330 mg Al/kg body weight per day (ATSDR, 2008).

In conclusion, based on this knowledge, no developmental toxicity effects are to be expected from the bioavailable fractions of Manganese or Aluminum which may potentially leach out the Spinel type lattice structure, if a PND study were conducted with the registered substance. Moreover, it can be stated that the amounts of Aluminum and Manganese, if absorbed from the limit dose of 1000 mg/kg body weight per day would not lead to foeto/embryotoxicity or teratogenicity in treated animals. Thus, no gain of knowledge can be obtained and the prenatal developmental toxicity study is considered as scientifically not justified and can be omitted according to Annex XI, Section 1.2 of the REACH Regulation.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

data waiving: supporting information

Reference

Endpoint:

sub-chronic toxicity: inhalation

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”.

Additionally, to the waiving arguments inserted in the section above, the Registrant commented ECHA draft decision from 07 May 2018 regarding the endpoint on sub-chronic toxicity study (90-day) and defined the following 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 will be outlined in the following, 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 will first be discussed in the following by Nos 1 through 4 and brought together for amalgamation into the weight of evidence approach as of Annex XI, Section 1.2.

1. Galaxite is a Spinel type mineral and does obviously lack any relevant reactivity, due to the fact, that its heavy metals are firmly bound within the Spinel type lattice. This practical inertness is proven by the very low water solubility (< 0.03 mg/L, calculated from the determined concentrations of Al and Mn of < 0.008 mg/L and 0.031 mg/L, respectively according to OECD guideline105) and high melting point (i.e. 1720 °C). Thus, the two criteria of an “unreactive and insoluble” substance are met.
2. Further, the registrant refers to the current ECHA’s draft decision (from 07/05/2018) to provide additional comments on the submitted information in the updated dossier.
In its decision, “ECHA considers that based on the information about differences in the particle sizes of the analogue magnesium dialuminium oxide, CAS 1302-67-6 / EC 215-105-9 (0.06 to 16 μm), and the registered substance (67μm - 2 mm), and its impact on the route of exposure, the newly provided read-across study is not relevant as part of the weight of evidence adaptation. This is due to the fact that the analogue substance is respirable and reaches the deep lungs, whereas inhalation is not relevant route of exposure for the registered substance.”

The registrant agrees that the 28-day study with the analogue substance may be considered not to be directly relevant because the respirable fraction of its particles is considerably smaller than the respirable fraction of the registered substance Galaxite.
Therefore, inhalation is consequently not a relevant route of exposure and above third criterion on a “not inhalable” substance is also met.
3. The criterion that “there is no evidence of absorption” is also met as reported in the bioaccessibility studies discussed below.
4. This leaves the last criterion on “no evidence of toxicity in a 28-day ‘limit test’” at a first approximation unanswered due to lack of respective inhalation data with Galaxite, because the registered substance`s particle size distribution is significantly divergent from that of the analogue substance; thus the registrant agrees that the cumulative conditions of the adaptation possibility of Annex IX, 8.7 Column 2 may formally not fully be fulfilled.
On the other hand, it needs to be considered and is strongly emphasized, that if an inhalation 28-day study would have been conducted with the registered substance at concentrations corresponding to the same amount of dust as tested with the analogue substance (if practically possible), effects on the respiratory tract could be expected to be even less pronounced because the substance, due to its particle sizes of 67 µm to 2 mm, would not reach the deep lung. Thus, the effects on the respiratory tract observed in the 28-day study with the analogue substance do actually represent a worst-case result for the registered substance Galaxite, if its particle sizes were in the same range as for the analogue substance, i.e. the criterion on “no evidence of toxicity in a 28-day ‘limit test’” is therefore indeed covered for Galaxite based upon the inhalation data with the analogue substance.
In this hypothetical case, it is also very likely that certain amounts of the substance would be swallowed, however no systemic effects are expected because the substance is of low bioavailability via all exposure routes. Thus, this 28-day study can still serve as a common piece of evidence supporting the generally low toxicological activity of Spinel type minerals.
The registrant therefore points out, that the above mentioned pieces of evidence together with the bioaccessibility study results (even though the registrant intends to repeat them due to certain shortcomings) are indeed sufficient to cover the information requirements according to general rules set out in Annex XI, section 1.2 (Weight of evidence).

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:

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 3

Reason / purpose for cross-reference:

data waiving: supporting information

Reference

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

other: An assessment of a hypothetical case that an inhalation study would have been conducted with the registered substance Galaxite.

Adequacy of study:

weight of evidence

Study period:

2018

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: expert assessment

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

according to guideline

Guideline:

other: expert statement

Deviations:

not applicable

GLP compliance:

no

Remarks:

not applicable

Key result

Dose descriptor:

conc. level:

Effect level:

0 mg/m³ air

Based on:

element

Remarks:

based on bioaccessibility of Al of 1.01 x 10-2 %

Sex:

not specified

Remarks on result:

other: calculated

Key result

Dose descriptor:

conc. level:

Effect level:

0 mg/m³ air

Based on:

element

Remarks:

based on bioaccessibility of Mn of 5.71 x 10-3%

Sex:

not specified

Remarks on result:

other: calculated

Key result

Critical effects observed:

no

Conclusions:

Based on the newly calculated bioaccessibility values of 1.01 x 10-2% for Aluminum and 5.71 x 10-3% for Manganese , 0.36 µg Al/m³ and 0.20 µg Mn/m³, respectively, would be theoretically bioavailable in animals (provided that bioavailability is grossly the same in animals and humans), if the registered substance were tested in a 28-day inhalation study, using the same concentrations as in the study with the source substance Spinel.

Executive summary:

Using the recalculated bioaccessibility values, the registrant evaluated the hypothetical case that an inhalation study would have been conducted with the registered substance Galaxite. The tested concentrations of 0.3, 0.95 and 2.77 mg/L in the 28-day study with the analogue substance would correspond to 0.38, 1.2 and 3.53 mg/L of the equivalent amount of the registered substance (calculated using molecular masses). At the highest concentration of 3.53 mg/L (3534 mg/m³), and accounting for the respirable fraction of 0.1%, 3.53 mg/m³ would be respirable dust that could reach deep lung areas. From this amount, accounting for the newly calculated bioaccessibility values, 0.36 µg Al/m³ would be theoretically bioavailable in animals (provided that bioavailability is grossly the same in animals and humans). This concentration is far below effect concentrations reported for soluble and less soluble Aluminum compounds (0.61 mg – 6.1 mg Al (elemental)/m³ for less serious effects, ATSDR, 2008) producing respiratory local and systemic effects in long-term inhalation animal studies.

For Manganese, 0.20 µg Mn/m³ would be bioavailable, the amount of which is also far below the lowest effect concentrations reported for soluble and less soluble Manganese compounds in aerosol/dust form (0.009 mg – 1.5 mg Mn (elemental)/m³; ATSDR, 2012) in long-term inhalation animal studies.

This comparison can also be used and consequently is actually to be used as a piece of evidence supporting the criterion of“no evidence of toxicity in a 28-day ‘limit test’”.

 

In conclusion, based on these theoretical considerations and taking into account the existing knowledge, no additional safety related information on local or systemic toxicity effects is to be expected if an inhalation long-term study with the registered substance Galaxite were to be conducted. The expected effects are only those associated with inhalation of inert, insoluble particulates and lung overload phenomena already reported in numerous animal studies with various Aluminum and Manganese compounds (including the study results with the analogue substance).

 

Cross-reference 4

Reason / purpose for cross-reference:

data waiving: supporting information

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

other: An assessment of a hypothetical case that an oral study would have been conducted with the registered substance Galaxite.

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:

reference to other study

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

reference to other study

Qualifier:

according to guideline

Guideline:

other: expert statement

Deviations:

not applicable

GLP compliance:

no

Remarks:

not applicable

Key result

Dose descriptor:

dose level:

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Remarks on result:

other: For Manganese and Aluminium, respectively, the bioavailable doses would be 6.9 and 0.06 mg/kg body weight per day.

Key result

Critical effects observed:

no

Conclusions:

For Manganese and Aluminium, originated from Galaxite, the bioavailable doses would be 6.9 and 0.06 mg/kg body weight per day, respectively, if an oral repeated dose toxicity study with the registered study were conducted. These doses are far below those producing adverse effects in animal studies with soluble and insoluble Aluminum and Manganese compounds.

Executive summary:

In case, a 90-day study with the registered substance would be conducted and the limit dose of 1000 mg/kg body weight per day be used, and, considering the newly calculated bioaccessibility values of 2.1 % and 0.02 % for Manganese and Aluminium, respectively, the bioavailable doses would be 6.9 and 0.06 mg/kg body weight per day. These dose levels are far below effect levels, LOAELs and NOAELs established for numerous Manganese and Aluminum compounds in animal oral toxicity studies. For Manganese compounds tested in repeated dose toxicity studies of intermediate exposure durations (up to 100 days), NOAEL values for systemic, including neurological, effects (neurotoxicity being the main health effect) were reported to be in the range of 15.1 – 1950 mg Mn/kg body weight per day (ATSDR, 2012). For Aluminum compounds tested in repeated dose toxicity studies of intermediate exposure durations (up to 100 days), NOAEL values were in the range of 52 -330 mg Al/kg body weight per day (ATSDR, 2008).The registrant is of the opinion, that this comparison can also be used as a piece of evidence supporting the criterion of“no evidence of toxicity in a 28-day ‘limit test”.

Cross-reference 5

Reason / purpose for cross-reference:

data waiving: supporting information

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.

Cross-reference 6

Reason / purpose for cross-reference:

data waiving: supporting information

Reference

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."

Results and discussion

Results (fetuses)

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified