Magnesium 2,3,4,5,6,7-Hexahydroxyheptanoate

Short-term toxicity to aquatic invertebrates

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

short-term toxicity to aquatic invertebrates

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The toxicity of glucoheptonate complexes is driven by the supplied metal cation that can affect mineral balance of the body, while no toxicity is attributed to the organic part of the molecule - glucoheptonate moiety - up to considerable amounts. Magnesium glucoheptonate is expected to dissociate from its complex, releasing metal cation - magneisum - at physiological pHs. So, glucoheptonate anion is fully protonated at low pH values and is not able to participate in complexation of metal cations: the stability constant of magnesium glucoheptonate is low, the chelate is a weak complex at normal environmental pH range (4-9) (Alekseev et al., 1998; please refer to the read-across statement). Therefore, the released equimolar amount of magnesium from magnesium glucoheptonate is expected to determine its toxicity to aquatic invertebrates. In this regard, the toxicity of magnesium originated from another magnesium compound could provide an additional information on toxicity of magnesium glucoheptonate. Therefore, the data on magnesium chloride hexahydrate is presented here as source of data for the target substance magnesium glucoheptonate to address the toxicity of metal cation.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
American Chemical Society reagent-grade magnesium chloride hexahydrate was used for the testing (99%).
Theorical composition of magnesium glucoheptonate (HGAMg (1:1), if water were extracted, is 78.0-82.4%; other component is Na2SO4: 17.6-21.2%.

Sodium and chloride are macroelements containing in considerable amounts in surface waters and in living organisms. Sulfur species are also in considerable amounts in living organisms. Thus, these cations and anions are considered not to impact the toxicity to aquatic invertebrates of magnesium.

3. ANALOGUE APPROACH JUSTIFICATION
As announced in the hypothesis for the read-across, magnesium glucoheptonate is expected to dissociate in aquatic environments (at normal pH range 4-9). Magnesium chloride hexahydrate is a salt that fully dissociates in water too. However, the amount of magnesium released from magnesium glucoheptonate and from magnesium chloride hexahydrate is different because the molecular masses of these compound are different . Also the proportion of magnesium to glucoheptonate or to chloride hexahydrate anions will be different. Additionally, hexahydrate is six water molecules that do not contribute to toxicity. As a result, more magnesium will be released from the salt magnesium chloride hexahydrate than from magnesium glucoheptonate. Thus, the data on magnesium chloride hexahydrate represent worst case for magnesium glucoheptonate.

4. DATA MATRIX
please refer to the detailled read-across statement attached in section 13.

Reason / purpose for cross-reference:

read-across source

GLP compliance:

no

Test organisms (species):

Daphnia magna

Duration:

48 h

Dose descriptor:

LC50

Remarks:

without food

Effect conc.:

273.7 mg/L

Nominal / measured:

meas. (geom. mean)

Conc. based on:

element (total fraction)

Remarks:

corresponding amount of magnesium moiety

Basis for effect:

other: complete immobilization or death

Remarks on result:

other: based on 6.1 % magnesium in magnesium glucoheptonate

Duration:

48 h

Dose descriptor:

LC50

Remarks:

with food

Effect conc.:

627.9 mg/L

Nominal / measured:

meas. (geom. mean)

Conc. based on:

element (total fraction)

Remarks:

corresponding amount of magnesium moiety

Basis for effect:

other: complete immobilization or death

Remarks on result:

other: based on 6.1 % magnesium in magnesium glucoheptonate

Calculation of corresponding effect/hazard levels for mahnesium glucoheptonate:

Molecular weight of magnesium glucoheptonate (1:1): 266.6 g/mol

Molecular weight of magnesium chloride heptahydrate: 203.3 g/mol

Molecular weight of magnesium: 24.31 g/mol

Molecular weight of glucoheptonate anion: 242.29 g/mol

According to molecular formulas, 1 mol magnesium moiety is contained in 1 mol magnesium chloride hexahydrate and in 1 mol magnesium glucoheptonate.

The LC50 (48 h) of 140 and 320 mg/L were established for magnesium chlorid hexahydrate with and without food administration regime in daphnia magna. Then the corresponding values for magnesium moiety originating from magnesium chloride hexahydrate would be as follows:

1) (140 x 24.31) / 203.3 = 16.7 mg Mg/L and (322 x 24.31) / 203.3 = 38.3 mg Mg/L;

The corresponding amounts of magnesium glucoheptonate are:

(16.7 x 266.6) / 24.31 = 183.14 mg/L with food and (38.3 x 266.6) / 24.31 = 420. 02 mg/L without food.

Estimation of hazard values for magnesium glucoheptonate based on total magnesium content in magnesium glucoheptonate :

The target substance Magnesium glucoheptonate contains 6.1 % Magnesium, which leads to the following conversion:

 

16.7 mg/L x 100 % / 6.1 % = 273.7 mg/L

38.3 mg/L x 100 % / 6.1.% = 627.9 mg/L

Although these values are higher than the values 183.14 and 420.02 mg/L calculated based on molecular weight, they are more realistic because the total content of metal in the product is the driving factor of toxicity.

Validity criteria fulfilled:

not specified

Remarks:

immobilised daphnids in the control not reported

Conclusions:

LC50 of 273.7 mg/L (without food).
LC50 of 627.9 mg/L (with food).

Executive summary:

The acute toxicity of Magnesium chloride hexahydrate (CAS 7791-18-6) towards Daphnia magna was determined in a study on the basis of a 48 -hour 50 % lethal concentration (LC50). A geometric series of concentrations were tested for obtaining an approximation of toxicity. Tests were run both with and without food additives as the food changed the toxicity values. The test was performed at least in triplicate. The test organisms (5 daphnids/test chamber) were exposed for 48 h to the test substance. The EC50 (48 h) value based on complete immobilization or death was determined to be 140 and 320 mg/L without and with food, respectively. Toxic effects were not specified.

Based on the read-across hypothesis, metal is the driving factor of toxicity. Therefore, LC50 values have been adapted taking into account molecular formulas of magnesium chloride hexahydrate and magnesium glucoheptonate. The corresponding amounts of magnesium glucoheptonate have been calculated also based on total fraction of magnesium (6.1 %) in the target substance:

The corresponding values for magnesium moiety originating from magnesium chloride hexahydrate would be as follows:

1) (140 x 24.31) / 203.3 = 16.7 mg Mg/L and (322 x 24.31) / 203.3 = 38.3 mg Mg/L;

The corresponding amounts of magnesium glucoheptonate would be:

(16.7 x 266.6) / 24.31 = 183.14 mg/L with food and (38.3 x 266.6) / 24.31 = 420. 02 mg/L without food.

Estimation of hazard values for magnesium glucoheptonate based on total magnesium content in magnesium glucoheptonate :

The target substance Magnesium glucoheptonate contains 6.1 % Magnesium, which leads to the following conversion:

 

16.7 mg/L x 100 % / 6.1 % = 273.7 mg/L

38.3 mg/L x 100 % / 6.1.% = 627.9 mg/L

Although these values are higher than the values 183.14 and 420.02 mg/L calculated based on molecular weight, they are more realistic because the total content of metal in the product is the driving factor of toxicity.

Reference 2

Endpoint:

short-term toxicity to aquatic invertebrates

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Sodium gluconate and magnesium glucoheptonate are structurally similar sugar-like substances with the same functional groups, whereby gluconate and glucoheptonate anions share similar chemical moiety. They differ only in one carbon segment (HCOH): glucoheptonate is longer (C7) than gluconate (C6). Gluconates and glucoheptonates are expected to dissociate from their respective salt or complex, releasing metal cations at physiological pHs. So, to address the toxicity of free of metal glucoheptonate anion to aquatic invertebrates, the data on gluconate is presented here. Furthermore, gluconate or glucoheptonate anion is fully protonated at low pH values and are not able to participate in complexation of metal cations (Alekseev et al., 1998; please refer to the read-across statement). Since the stability constant of magnesium glucoheptonate is low, the chelate is a weak complex at normal environmental pH range (4-9). Sodium gluconate is a salt that freely dissociates to sodium cation and gluconate anion in water. Therefore, it is expected that free gluconate and glucoheptonate anions appears in equal amounts from the salt or complex, respectively. Moreover, the toxicity of gluconate and glucoheptonate salts or complexes is driven by the supplied metal cation that can affect mineral balance of the body, while no toxicity is attributed to gluconate or glucoheptonate moiety up to considerable amounts. Additionally, gluconates and glucoheptonates are believed to be metabolised by the same mechanisms by microorganisms and by other classes of living organisms. Therefore their toxicity to aquatic invertebrates is expected to be similar.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Purity of sodium gluconate is generally above 97 % (OECD SIDS, 2004). The rest is water.
Theorical composition of magnesium glucoheptonate (HGAMg (1:1), if water were extracted, is 78.0-82.4%; other component is Na2SO4: 17.6-21.2%. Sodium is the same originating from Na2SO4 and from the source substance sodium gluconate, thus the only difference in the impurities is sulphate. Sulphate is considered not to impact toxicity of magnesium glucoheptonate to aquatic invertebrates to a significant extent because sulfur species are in considerable amounts in living organisms.

3. ANALOGUE APPROACH JUSTIFICATION
Gluconates and glucoheptonates are naturally occurring substances that are metabolised by pentose phosphate pathway.

4. DATA MATRIX
please refer to the detailled read-across statement attached in section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

reference to other study

Reference substance (positive control):

not required

Duration:

48 h

Dose descriptor:

NOEC

Effect conc.:

> 1 000 mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

not specified

Remarks on result:

other: expected to be valid for glucoheptonate anion.

Duration:

48 h

Dose descriptor:

EC100

Effect conc.:

> 1 000 mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

not specified

Remarks on result:

other: expected to be valid for glucoheptonate anion.

Duration:

48 h

Dose descriptor:

EC50

Effect conc.:

> 1 000 mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

not specified

Remarks on result:

other: expected to be valid for glucoheptonate anion.

Duration:

24 h

Dose descriptor:

NOEC

Effect conc.:

> 1 000 mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

not specified

Remarks on result:

other: expected to be valid for glucoheptonate anion.

Duration:

24 h

Dose descriptor:

EC100

Effect conc.:

> 1 000 mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

not specified

Remarks on result:

other: expected to be valid for glucoheptonate anion.

Duration:

24 h

Dose descriptor:

EC50

Effect conc.:

> 1 000 mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

not specified

Remarks on result:

other: expected to be valid for glucoheptonate anion.

Details on results:

No details given.

Results with reference substance (positive control):

Not applicable.

Reported statistics and error estimates:

No details given.

Calculation of corresponding effect/hazard levels for glucoheptonate anion:

Molecular weight of magnesium glucoheptonate (1:1): 266.6 g/mol

Molecular weight of sodium gluconate: 218.14 g/mol

Molecular weight of sodium: 22.99 g/mol

Molecular weight of glucoheptonate anion: 242.29 g/mol

Provided that 1 mol of gluconate and glucoheptonate anions bind metals as 1:1, the weight of 1 mol of glucoheptonate is more than the weight of 1 mol of gluconate anion. Thus, the corresponding weight of 1 mol magmesium glucoheptonate is more than that of sodium gluconate.

The hazard values EC50, EC100, NOEC (24 and 48 h) are greater than 1000 mg/L for sodium gluconate. Then the corresponding values for glucoheptonate anion originating from magnesium glucoheptonate would be as follows:

1) 105.39 mg sodium is contained in 1000 mg sodium gluconate: (1000 x 22.99) / 218.14; and 1000 - 105.39 = 894.6 mg gluconate anion.

2) If 894.6 mg was glucoheptonate anion, it would correspond to 984.3 mg of magnesium glucoheptonate (894.6 x 266.6) / 242.29;

3) On the other hand, if 1000 mg was magnesium glucoheptonate, the weight of glucoheptonate moiety would be (1000 x 242.29) / 266.6 = 908.8 mg.

Comparing the weight of gluconate vs glucoheptonate moieties in 1000 mg: 894.6 mg vs. 908.8 mg, the values are close to each other. Therefore, it is expected that the hazard from glucoheptonate anion would not be higher than that from gluconate anion.

Estimation of hazard values for magnesium glucoheptonate:

In respect to cation moiety, the corresponding amount of magnesium containing in 1000 mg of magnesium glucoheptonate is: 1000 - 908.8 = 91.2 mg /L. This amount is higher than the lowest hazard value (LC50 of 16.7 and 38.3 mg Mg moiety/L, corresponding to 140 and 320 mg Magnesium chloride hexahydrate/L with and without food, tested to daphnia magna; (Biesinger and Christensen, 1972, please refer to cross references in this section).

Therefore, a toxicity of magnesium glucoheptonate to daphia magna cannot be ruled out at hazard values established for sodium gluconate > 1000 mg/L.

Validity criteria fulfilled:

not specified

Remarks:

immobilised daphnids in the control not reported

Conclusions:

The quantity of glucoheptonate anion is not expected to pose risk to aquatic invertebrates at EC50/NOEC (48 h) > 1000 mg/L (based on nominal concentration) established for sodium gluconate.

Executive summary:

The acute toxicity of the source substance Sodium gluconate (CAS 527-07-1) towards Daphnia magna has been determined according to OECD Guideline 202 in compliance with GLP. After the range-finding study (2 vessels/concentration, 10 daphnids/concentration), the definitive test was conducted with test concentrations of 0 (control) and 1000 mg/L (limit test). The measured concentrations of the test substance in the test solution were within +/- 20% of the nominal concentration in all concentrations (HPLC technique has been used).

The EC50/NOEC (48 h) value amounts to > 1000 mg/L based on the nominal test concentration.

The data on sorce substance is presented here to cover toxicity of organic part of the molecule - glucoheptonate anion.

Since gluconate and glucoheptonate anions are naturally occurring substances and are both intermediates in the carbohydrate metabolism, their toxicity to aquatic environment is expected to be similar. Therefore, the EC50/NOEC (48 h) value of greater than 1000 mg/L is also applicable for corresponding amounts of glucoheptonate anion originating from magnesium glucoheptonate. Additionally, since according to the read-across hypothesis, the toxicity to aquatic life is driven more by the applied metal cation and not by glucoheptonate anion, the toxicity of the corresponding amounts of magnesium originating from 1000 mg/l of magnesium glucoheptonate, if the target substance was tested, were compared to the known hazard values established for magnesium moiety from inorganic salts.

In respect to cation moiety, the corresponding amount of magnesium containing in 1000 mg of magnesium glucoheptonate is: 1000 - 908.8 = 91.2 mg /L. This amount is higher than the lowest hazard value (LC50 of 16.7 and 38.3 mg Mg moiety/L, corresponding to 140 and 320 mg Magnesium chloride hexahydrate/L with and without food, tested to daphnia magna; (Biesinger and Christensen, 1972, please refer to cross references in this section).

Therefore, a toxicity of magnesium glucoheptonate to daphia magna cannot be ruled out at hazard values established for sodium gluconate > 1000 mg/L.

Description of key information

OECD SIDS, 2004_OECD 202_Daphnia magna: EC50 (48 h) > 1000 mg/L [Sodium gluconate]
Biesinger and Christensen_OECD 202_Daphnia magna_ EC50 (48 h) = 16.7 mg Mg/L [Magnesium]; EC50 (48 h) = 273.77 mg/L [Magnesium glucoheptonate]

The studies with the lowest hazard values for gluconate and magnesium have been chosen for the calculation of an equivalent exposure concentration for the target substance magnesium glucoheptonate.

Key value for chemical safety assessment

Fresh water invertebrates

Fresh water invertebrates

Effect concentration:

273.77 mg/L

Additional information

There is no data available for the target substance Magnesium glucoheptonate (CAS 1821694 -26 -1) on acute toxicity towards invertebrates. However, there is data available for the source substance Sodium gluconate (CAS 527-07-01). The data on acute toxicity for magnesium inorganic compounds (Magnesium chloride; Magnesium sulphate) was also taken into account to address toxicity of magnesium which would release from the magnesium glucoheptonate complex and to quantify an exposure concentration for the target substance Magnesium glucoheptonate.

Data on sodium gluconate

As key information, the acute toxicity of the source substance Sodium gluconate (CAS 527-07-1) towards Daphnia magna has been determined according to OECD Guideline 202 in compliance with GLP (OECD SIDS, 2004). After the range-finding study (2 vessels/concentration, 10 daphnids/concentration), the definitive test was conducted with test concentrations of 0 (control) and 1000 mg/L (limit test). The measured concentrations of the test substance in the test solution were within +/- 20% of the nominal concentration in all concentrations (HPLC technique has been used). The EC50/NOEC (48 h) value amounts to > 1000 mg/L based on the nominal test concentration.

As supporting information, the acute toxicity of the source substance Sodium gluconate (CAS 527-07-1) towards Daphnia magna was determined according to OECD Guideline 202 in compliance with GLP (OECD SIDS, 2004). A limit test with 1000 mg/L was conducted. The test organisms (5 daphnids/vessel) were exposed for 48 h to the test substance. The EC50 (48 h) value based on mobility was determined to be > 1000 mg/L. Toxic effects were not observed.

Data on magnesium salts

As key information for the magnesium cation, the acute toxicity of Magnesium chloride hexahydrate (CAS 7791 -18 -6) towards Daphnia magna was determined in a study on the basis of a 48 -hour 50 % lethal concentration (LC50) (Biesinger and Christensen, 1972). A geometric series of concentrations were tested for obtaining an approximation of toxicity. Tests were run both with and without food additives as the food changed the toxicity values. The test was performed at least in triplicate. The test organisms (5 daphnids/test chamber) were exposed to the test substance during 48 hours. The EC50 (48 h) value based on complete immobilization or death was determined to be 140 and 320 mg/L without and with food, respectively. Toxic effects were not specified. Taking the molecular weights of Magnesium chloride hexahydrate (MW = 203.3 g/mol) and Magnesium (MW = 24.3 g/mol) into account, the EC50 (48 h) values are converted to 16.7 and 38.3 mg Mg/L.

In a supporting study, Mysid shrimp (Mysidopsis bahia) was exposed to saline solutions containing excess magnesium during 48 hours (Pillard et al., 2000). The maximum concentration tested was 21.746 g/L that was 4.88 higher than the concentration in the modified GP2 artificial seawater. Solution salinity was maintained at approximately 31‰ by increasing or decreasing sodium and chloride concentrations. Logistic regression models were developed with both the ion molar concentrations and ion activity. Toxicity was observed when either a deficiency or an excess of potassium and calcium occurred. Significant mortality occurred when the tested species were exposed to excess concentrations of magnesium. LC 50(48 h) = 2650 mg Mg/L and NOEC (48 h) = 2480 mg Mg/L were estimated based on molarity models.

In another supporting study, Mysid shrimp (Americamysis bahia) was exposed to saline solutions containing excess magnesium during 48 hours (Pillard et al., 2002). The maximum concentration tested was 5 times higher than the concentration in the modified GP2 artificial seawater. The test was conducted at salinity of 10 and 20‰. LC50s were calculated using trimmed Spearman-Karber program and estimated from the logistic models. The both LC50 were similar with each other. The tolerance of mysid shrimp to higher concentrations of Mg2+ increased as the test salinity increased, as evidenced by the NOAECs and LC50s:

NOAEC (48 h) = 739.56 mg Mg/L (at salinity of 10 ‰);

NOAEC (48 h) = 1479.12 mg Mg/L (at salinity of 20 ‰);

LC 50 (48 h) = 832 and 1705.18 mg Mg/L at salinity of 10 and 20 ‰, respectively (TSK calculated method);

LC 50 (48 h) = 787.71 and 1609.45 mg Mg/L at salinity of 10 and 20 ‰, respectively (estimated directly from the logistic models).

In another supporting study, MgSO4 was tested in a static-renewal acute toxicity test with Daphnia magna (Meyer et al., 1985). The test followed standard practices for toxicity testing with macroinvertebrates (ASTM Protocol E 729 -80). The test was performed to determine if the inorganic salt contributed to the observed toxicity of raw shale leachates. The salt was diluted with a mixture of well water and dechlorinated city water. The experiment was conducted in triplicate. 10 organisms (neonates: < 24 h old) were placed in each 50 -mL solution for 48 hours at 20 °C. All tests were conducted under a 16-h light: 8-h dark photoperiod. Every 24 h, survival and activity levels of test animals were observed. Dead organisms were removed at that time, and survivors were transferred to fresh exposure solutions. LC50 of 4300 mg/L was determined for Magnesium sulphate. LC50 of 868 mg/L was then calculated for Mg element based on molecular weights of 120.366 and 24.3 g/mol for Magnesium sulphate and Magnesium, respectively.

In another supporting study (Mount et al., 1997), Daphnia magna (5 organisms/chamber) were exposed during 48 hours to different concentrations of MgSO4 (reagent grade). The study was conducted according to the general guidance of US EPA for conducting acute whole effluent toxicity tests (4th ed. EPA/600/4-90/027). Stock solution was prepared by dissolving 10,000 mg/L of the salt in moderately hard reconstituted water (MHRW). Test solutions were prepared by serially diluting the stock solution with MHRW to develop a series of test concentrations spaced on a 0.5 dilution factor (i.e., 10,000, 5,000, 2,500, 1,250 mg/L). As testing proceeded and effect thresholds were determined, test concentrations were often spaced much more closely (e.g., 2,500, 2,000, 1,500, 1,000, 500 mg/L) to better define responses near the effect threshold. The daphnids were fed by a 1:1 mix of YCT and algal suspension (100 µLwas added to each test chamber at test initiation). Based on the study results, a LC50 of 1820 mg/L was calculated for MgSO4. The LC50 for element Magnesium was calculated based on the MW of 120.366 and 24.3 g/mol for Magnesium sulphate and Magnesium, respectively.

Derivation of effective concentrations for Magnesium glucoheptonate (CAS 1821694-26-1)

There are two key study available for the source substance Sodium gluconate (CAS 527-07-1) and the salt Magnesium chloride hexahydrate (CAS 7791-18-6). Although it is expected that toxicity of the target substance is rather triggered by the magnesium cation, data on a gluconate are also considered for the Chemical Safety Assessment.

 

An EC50 (48 h) of > 1000 mg/L and a NOEC (48 h)of 1000 mg/L were determined for the substance Sodium gluconate (OECD SIDS, 2004).

 

The most critical effect concentration for magnesium has been determined by Biesinger and Christensen (1972). An EC50 value (48 h) of 16.7 mg Mg/L has been calculated for Daphnia magna.

 

The target substance Magnesium glucoheptonate contains 6.1 % Magnesium, which leads to the following conversion.

 

16.7 mg/L x 100 % / 6.1 % = 273.7 mg/L

 

The calculated EC50 (48 h) value of 273.77 mg/L for the target substance is lower than the EC50/NOEC determined for Sodium gluconate (CAS 527 -07 -1). Thus, this value will be used for the Chemical Safety Assessment.