Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics, other
Remarks:
Expert statement
Type of information:
other: assessement of toxicokinetic behaviour based on physico-chemical properties and toxicological data
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: An assessment of the toxicokinetic behaviour of the magnesium metaborate target substance was performed, taking into account the chemical structure, the available physico-chemical-data and the available toxicological data.

Data source

Reference
Reference Type:
other: Expert statement
Title:
Unnamed
Year:
2018
Report Date:
2018

Materials and methods

Objective of study:
absorption
distribution
excretion
metabolism
Test guideline
Qualifier:
according to
Guideline:
other: Technical guidance document, Part I, 2003; ECHA guidance R7C., 2014
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Test material form:
liquid

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
An oral absorption value of 100 % is considered appropriate for the purposes of hazard assessment for this compound. 100 % inhalation absorption and 10 % dermal absorption are considered as worst-case values. The borate absorption via skin is 0.2%.
Type:
distribution
Results:
A quick and wide distribution of boric acid and magnesium ion can be expected.
Type:
metabolism
Results:
Boric acid is not metabolised due to the energy barrier (523 kJ/mol) required to break the boron–oxygen bond in inorganic borates (Murray, 1998; EFSA, 2013).
Type:
excretion
Results:
The elimination of magnesium and boric acid occurs mainly via the kidneys as urine. The amount not absorbed from the gastrointestinal tract is excreted in the faeces

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Oral absorption
The registered substance consists of magnesium ion bound to two metaborates. Metaborate anion is the main species of boric acid in solution at a pH of above 10 (IPCS, 1998; WHO, 2009). This is underlined by the fact that the pH of an aqueous solution of Sodium metaborate at 20°C ranges from 10.5 at 0.1% w/w to 12.0 at 18% w/w (IPCS 1998). Due to its pKa of 9.15, boric acid exists predominantly as undissociated boric acid (B(OH)3) in aqueous solutions below pH 7 (IPCS, 1998; WHO, 2009). This is independent of whether the boron source is boric acid (H3BO3) or borate (EFSA 2004). Therefore, borates and boric acid have similar absorption potentials (IPCS, 1998; WHO, 2009). Based on these findings, it is likely, that magnesium metaborate will dissociate in the acidic environment of the stomach to boric acid and magnesium ion. Due to the known toxicity of borates (EFSA 2013, IPCS 1998 and others), the toxic effects of magnesium metaborate are expected to be mainly caused by the metaborate moiety, occurring as boric acid at physiological pH (HERA 2005). With a log P value of 0.175 (EVM, 2002) and a molecular weight of 62 g/mol the absorption route of boric acid is most likely via passive diffusion through aqueous pores of the gastrointestinal epithelial by the bulk passage of water. The absorption of borates has shown to be essentially complete (approximately 95% in humans and rats), and boron appears rapidly in the blood and body tissues of several mammalian species following ingestion (IPCS 1998).
The toxicological profile of the registered substance reveals severe systemic toxicity in rats after oral exposure (gavage) to 300 mg/kg/day. As described above, toxic effects were observed in testes, adrenal glands, thymus and liver (Herberth, 2016). The severe toxic effects on reproduction found after exposure to the registered substance equal the toxicological profile of boric acid (Ku et al., 1993; Fail et al. 1991 and others). This provides evidence that a significant amount of boric acid partitioned into the blood circulation after ingestion of the test item.
Magnesium is absorbed from the gastrointestinal tract by the blood at an amount of about 50 % (WHO, 2009) via passive diffusion through aqueous pores of the gastrointestinal epithelial by the bulk passage of water.
Based on this information, the worst case absorption value of 100 % is considered appropriate for the purposes of hazard assessment for this compound.

Dermal absorption
Absorption in the Stratum corneum is favoured for substances with a molecular weight of below 100 g/mol and very unlikely for chemicals with a molecular weight of above 500 g/mol. To cross the lipid-rich Stratum corneum a certain degree of lipophilicity is required (Log P > 0). The active ingredient of the registered substance has a molecular weight of 110 g/mol. The log P of the registered substance was not determinable. However, in the registered substance the active ingredient magnesium metaborate is diluted in 53 % mineral oil. Therefore, the registered substance is expected to be lipophilic. Based on the moderate molecular weight and the lipophilicity, the registered substance might be able to be absorbed by the Stratum corneum. To partition from the Stratum corneum into the viable part of the epidermis, a substance must be sufficiently soluble in water. Therefore, if the water solubility is below 1 mg/l, dermal uptake is likely to be low. The registered substance has a water solubility of 1E-4 mg/L. Thus, penetration into the deeper, viable layers of the epidermis is unlikely. This is underlined by an “Acute Dermal Toxicity (Limit Test) in the Rat” (OECD Guideline 402, GLP) performed with the registered substance. After a single dermal application (24 hours) of the undiluted test item to intact skin at a dose level of 2000 mg/kg body weight, the test organisms did not show any signs of systemic toxicity (Sanders, 2016). The fact, that animal skin is generally more permeable than human skin (Hoaeng 1992), dermal absorption is unlikely.
Since magnesium is a major nutrient and is a normal constituent of the human body up to considerable amounts, no hazard is expected from the quantities of magnesium which can be absorbed from the respective amounts of magnesium metaborate.
In conclusion, no significant dermal absorption is expected for the registered substance. Under neutral and slight lower pH, which is the case for skin, magnesium metaborate can be considered to hydrolyze to magnesium hydroxide and boric acid. Absorption of borates via the skin is very low (0.2% for borates). The value was established for borate compounds based on in vitro and in vivo studies in animals and in humans (Wester et al. 1998). The LD50 of > 2000 mg/kg bw for magnesium metaborate confirms the low absorption potential of borates and provides evidence that sulfonic acid and mineral oil constituents do not influence the absorption potential of metaborate ion to such extent that it exerts its systemic toxicity.

Respiratory absorption
Due to the low volatility (vapour pressure of 0.04 Pa at 25°C) the registered substance is unlikely to be available for inhalation as a vapour. In addition, as the substance is a liquid, no inhalable particles occur. Thus, it is very unlikely that considerable amounts of the substance reach the lung. In case, the chemical reaches the lung, penetration to the lower respiratory tract is favoured by its low molecular weight and its insolubility in water (0.1 mg/L). The low water solubility prevents the substance from dissolving in the mucus lining the respiratory tract. Supposing that however small amounts dissolve in the mucus, the metaborate moiety will likely dissociate to boric acid. It has been shown that at low concentrations, inorganic borates can be converted to boric acid at physiological pH in the aqueous layer overlying mucosal surfaces prior to absorption (IPCS, 1998). Boric acid has a log P of 0.175 (EVM, 2002). Thus, absorption directly across the respiratory tract epithelium by passive diffusion is favoured.
Magnesium is able to be absorbed via passive diffusion through aqueous pores. However, the respective amounts of magnesium are expected to be very low. Moreover since the substance is not expected to be volatile, no hazard is associated with the absorbed magnesium.
Based on this data, inhalatory exposure is unlikely. If respiratory exposure takes place, a moderate to high systemic availability can be predicted. As worst case, 100 % inhalation absorption as default guidance value is appropriate.
Details on distribution in tissues:
Since the metaborate moiety dissociates from magnesium in the stomach forming boric acid before absorption, the distribution and accumulative potential of magnesium and boric acid can follow more or less independent ways. As mentioned before, boric acid has a log P value of 0.175 (EVM, 2002) and a molecular weight of 62 g/mol. Thus, it might partition into the blood circulation via passive diffusion. Most of the simple inorganic borates exist predominantly as un-dissociated boric acid in dilute aqueous solution at physiological pH, leading to the conclusion that the main species in the plasma of mammals is un-dissociated boric acid (HERA 2005). Several studies have shown that boric acid is toxic to reproduction (Ku et al., 1993; Fail et al. 1991 and others). This is equivalent to the results of the reproduction-toxicity study with magnesium metaborate (Herberth, 2017). The low molecular weight of boric acid (62 g/mol) favours a wide distribution. Due to the slight lipophilic properties (log P > 0), boric acid is likely to pass cell membranes and thus being distributed within cells. Significantly increased boron concentrations were detected in the brain of rats after exposure to boric acid (Mosemann, 1993). This shows that boric acid is able to pass the blood-brain barrier. Toxic effects in rats after exposure to the registered substance were observed in testes, adrenal glands, thymus and liver (Herberth 2016). It also revealed neonatal toxicity (Herberth, 2017) indicating the ability of boric acid to pass the placenta.
Magnesium is distributed widely through the body via blood circulation. It is able to diffuse through aqueous channels and pores and is transported with the aid of transporters into cells.
As a conclusion, a quick and wide distribution of boric acid and magnesium ion can be expected.

Accumulation
Besides the adverse toxic effects, a dark red discoloration of the adrenal glands was observed in the 13-Day Oral (Gavage) Toxicity Study in Rats (Herberth 2016). This can be an indication for accumulation of boric acid in adrenal glands. Further indications for accumulation are not found in this study. Due to the moderate logP of boric acid (0.175, EVM 2002; cited by EFSA 2013), no accumulation in fatty tissues is expected.
Mosemann (1993) analysed several hundred rat tissue samples from two studies (Ku et al., 1991 and Treinen et al., 1991) for boron. It was observed, that boron accumulates in bones after exposure to boric acid. After the first day of the diet with boric acid, the boron content of bone increased 20-fold. However, the concentration in bone decreased rapidly when the rats were removed from the 9000-ppm boric acid diet. In contrast to the bones, the soft tissues did not contain boron at levels substantially above that found in blood. The adverse reproductive effects in male rats, and the visible testicular lesions, do not appear to be the result of accumulation of very high concentrations of boron in the testis or other reproductive organs. The levels of boron in these tissues are not higher than the boron found in blood and the other soft tissues of the exposed animals (Mosemann, 1993).
Magnesium does not accumulate in people with normal kidney function. The major cause of hypermagnesemia is renal insufficiency associated with a significantly decreased ability to excrete magnesium (WHO, 2009).
In conclusion, the only relevant accumulation sites of magnesium metaborate are bones. Here, a significant increase of the boron content is induced.
Details on excretion:
Due to the high absorption rate of boric acid into the blood, the main excretion route is expected to be via the kidneys as urine. This is underlined by a study performed by Wiley (1917). He studied the excretion of boric acid in 15 young men. The total quantity of boric acid (and borax as boric acid), administered during the investigation was 607.4 g, of which 468.69 g were recovered in the urine, the average percentage recovered being 77.I6 %. The total quantity of boric acid excreted in the feces and perspiration is at about 3 % (Wiley, 1917).
Boric acid is not metabolised due to the energy barrier (523 kJ/mol) required to break the boron–oxygen bond in inorganic borates (Murray, 1998; EFSA, 2013). This is supported by evidence in both human and animal studies, where more than 90 % of an administered dose of borate is excreted as boric acid (IPCS, 1998). Murray (1998) analysed the kinetics of elimination in human volunteers given boric acid orally or intravenously. The primary route of elimination was found to be by glomerular filtration. The half-life for elimination was essentially at about 21 h by either route of exposure (Murray, 1998). Litowitz et al. (1988) found a half-life of 4 to 27.8 hours in nine humans, who ingested an acute amount of boric acid (up to 340 μg/mL).
As mentioned before, approximately 50 % of the ingested magnesium is absorbed in the blood (WHO, 2009). The elimination of this part occurs via the kidneys as urine. The amount not absorbed from the gastrointestinal tract is excreted in the faeces.

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
Boric acid is not metabolised due to the energy barrier (523 kJ/mol) required to break the boron–oxygen bond in inorganic borates (Murray, 1998; EFSA, 2013). This is supported by evidence in both human and animal studies, where more than 90 % of an administered dose of borate is excreted as boric acid (IPCS, 1998).

Any other information on results incl. tables

There are no ADME studies available for magnesium metaborate. The toxicokinetic profile was not determined by actual absorption, distribution, metabolism or excretion measurements. Rather, toxicokinetics of magnesium metaborate was assessed based on the physical-chemical properties in combination with results of toxicity studies. Additionally, publications on the derivative boric acid were integrated to create a prediction of the toxicokinetic behaviour, because the systemic toxicity of magnesium metaborate is considered to be driven by released boric acid.

Table 1: Physical-chemical properties of magnesium metaborate the derivative boric acid

Structure

B2HO4Mg (active ingredient)

Boric acid

Molecular Weight

109.9 g/mol (active ingredient)

61.8 g/mol

Vehicle

Mineral oil (53 %)

 

Physical state

liquid

powder

Water Solubility (20 °C)

< 0.1 mg/L

47 g/L (NCBI database)

Log P

Not determinable

0.175 (EVM, 2002; cited by EFSA 2013)

pKa

 

9.15 (IPCS, 1998; WHO, 2009)

Vapour Pressure

25°C->3.65 x 10E-2 Pa

40°C->9.19 x 10E-2 Pa

70°C->0.608 Pa

 

Toxicological profile

With the registered substance (19.57% magnesium metaborate (Active Ingredient), 27.43% magnesium sulfonate, and 53% mineral oil) one acute and two repeated-dose studies were performed (13-day, 28 day with Reproduction/Developmental Toxicity Screening).

Acute Oral Toxicity in the Rat – Fixed Dose Method (OECD Guideline 420, GLP) (Sanders 2017)

Study design

Following a sighting test at a dose level of 2000 mg/kg, an additional four fasted female animals were given a single oral dose of test item at a dose level of 2000 mg/kg bw. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy.

Conclusion

One dose of 2000 mg/kg body weight did not lead to systemic toxicity in four Wistar strain rats.

A 13-Day Oral (Gavage) Toxicity Study in Rats (Herberth 2016)

Study design

The test substance was administered orally by gavage to 4 groups Crl:CD(SD) rats, each group consisting of 5 males and 5 females, once daily for 13 consecutive days. Arachis oil was used as vehicle. Dosage levels were 100, 300, 500, and 1000 mg/kg/day administered at a dose volume of 10 mL/kg. A concurrent control group composed of 5 rats/sex received the control substance arachis oil and mineral oil mixture on a comparable regimen The percentage of mineral oil matched that in the high-dosage group.

Conclusion

Excessive toxicity was observed at 1000 mg/kg/day as evidenced by mortality, clinical observations, mean body weight losses, lower mean body weights, and lower mean food consumption which resulted in early group termination of the remaining animals on study day 5. In the 500 mg/kg/day group, macroscopic findings included dark red discoloration of the adrenal glands and small thymus for males and females and pale liver for females. Dark red discoloration of the adrenal glands was also noted for males at 300 mg/kg/day. In addition, lower mean absolute and relative (to final body and brain weights) thymus weights were noted in a dose-responsive pattern for males in the 100, 300, and 500 mg/kg/day groups and females in the 300 and 500 mg/kg/day groups, which correlated with macroscopic findings of small thymus in the 300 and 500 mg/kg/day groups. Lower mean liver weights (absolute and relative to final body and brain weights) were noted for males in the 500 mg/kg/day group and corresponded with lower body weight.

Combined 28-Day Repeated Dose Oral (Gavage) Toxicity Study with Reproduction/Developmental Toxicity Screening Test in Rats, with Recovery (OECD Guideline 422, GLP) (Herberth, 2017)

Study Design

The test substance in the vehicle arachis oil was administered orally by gavage once daily to 4 groups of Crl:CD(SD) rats. The low- and mid-dose groups (Groups 2-4) each consisted of 10 rats/sex and the high-dose group (Group 5) consisted of 15 rats/sex. Dosage levels were 15, 50, 125, and 300 mg/kg/day. A concurrent control group of 15 rats/sex received the control article arachis oil and mineral oil mixture on a comparable regimen. The percentage of mineral oil matched that in the high-dosage group. The dose volume was 10 mL/kg for all groups.

Conclusion

Under the conditions of this screening study, test substance-related effects on F0 male reproductive organs were noted at 300 mg/kg/day. Macroscopic findings of small and/or soft testes and epididymides corresponded with lower mean testes and epididymal weights and microscopic findings of reduced luminal sperm (epididymides) and tubular degeneration (testes) and were of greater magnitude at the recovery necropsy. In addition, a test substance-related longer gestation length was noted at 300 mg/kg/day, therefore, a dosage level of 125 mg/kg/day was considered to be the no-observed-adverse-effect level (NOAEL) for male and female reproductive toxicity when administered orally by gavage to Crl:CD(SD) rats. Under the conditions of this screening study, the NOAEL for systemic toxicity was considered to be 125 mg/kg/day based on lower body weights, body weight gains, and reduced food consumption in the 300 mg/kg/day group males and females. The NOAEL for neonatal toxicity was 50 mg/kg/day based on lower pup body weights and body weight gains at 125 and/or 300 mg/kg/day.

Applicant's summary and conclusion

Conclusions:
Magnesium metaborate is expected to be moderately absorbed after oral exposure, based on its low water solubility (> 0.1 mg/L) and low molecular weight (109 g/mol). As worst-case 100 % oral absorption is considered appropriate. Concerning absorption exposure via inhalation, the substance is poorly available for inhalation, due to its low vapour pressure. However, the low water solubility is favourable for penetration in the alveolar regions of the lung. Absorption, after dissolving in the mucus lining the respiratory tract (most probably in the form of boric acid) cannot be ruled out. Therefore, 100 % inhalation absorption is considered as worst-case. Magnesium metaborate can potentially be absorbed by the Stratum corneum. Partition into the deeper viable parts of the epidermis is unlikely due to the low water solubility. This was also demonstrated in a key study with rats, where no systemic absorption after dermal exposure was observed. 10 % absorption is considered. Magnesium metaborate occurs in the body most likely in the un-dissociated form as boric acid and magnesium ion. Boric acid and magnesium ion are not further metabolised. They are expected to be distributed widely with the blood circulation. Boric acid is suggested to accumulate in the bones. Magnesium and boric acid are excreted mainly via the kidneys as urine.
Executive summary:

There are no ADME studies available for magnesium metaborate. The toxicokinetic profile was not determined by actual absorption, distribution, metabolism or excretion measurements. Rather, toxicokinetics of magnesium metaborate was assessed based on the physical-chemical properties in combination with results of toxicity studies. Additionally, publications on the derivative boric acid were integrated to create a prediction of the toxicokinetic behaviour, because the systemic toxicity of magnesium metaborate is considered to be driven by released boric acid.

It is likely, that magnesium metaborate will dissociate in the acidic environment of the stomach to boric acid and magnesium ion. Due to the known toxicity of borates (EFSA 2013, IPCS 1998 and others), the toxic effects of magnesium metaborate are expected to be mainly caused by the metaborate moiety, occurring as boric acid at physiological pH (HERA 2005). With a log P value of 0.175 (EVM, 2002) and a molecular weight of 62 g/mol the absorption route of boric acid is most likely via passive diffusion through aqueous pores of the gastrointestinal epithelial by the bulk passage of water. The absorption of borates has shown to be essentially complete (approximately 95% in humans and rats), and boron appears rapidly in the blood and body tissues of several mammalian species following ingestion (IPCS 1998). Magnesium is absorbed from the gastrointestinal tract by the blood at an amount of about 50 % (WHO, 2009) via passive diffusion through aqueous pores of the gastrointestinal epithelial by the bulk passage of water.

Based on this information, the worst case absorption value of 100 % is considered appropriate for the purposes of hazard assessment for this compound.

No significant dermal absorption is expected for the registered substance. Under neutral and slight lower pH, which is the case for skin, magnesium metaborate can be considered to hydrolyze to magnesium hydroxide and boric acid. Absorption of borates via the skin is very low (0.2% for borates). The value was established for borate compounds based on in vitro and in vivo studies in animals and in humans (Wester et al. 1998). The LD50 of > 2000 mg/kg bw for magnesium metaborate confirms the low absorption potential of borates and provides evidence that sulfonic acid and mineral oil constituents do not influence the absorption potential of metaborate ion to such extent that it exerts its systemic toxicity.

Inhalatory exposure is unlikely. If respiratory exposure takes place, a moderate to high systemic availability can be predicted. As worst case, 100 % inhalation absorption as default guidance value is appropriate.

Magnesium is distributed widely through the body via blood circulation. It is able to diffuse through aqueous channels and pores and is transported with the aid of transporters into cells.

Magnesium does not accumulate in people with normal kidney function. The major cause of hypermagnesaemia is renal insufficiency associated with a significantly decreased ability to excrete magnesium (WHO, 2009). In conclusion, the only relevant accumulation sites of magnesium metaborate are bones. Here, a significant increase of the boron content is induced. Approximately 50 % of the ingested magnesium is absorbed in the blood (WHO, 2009). The elimination of this part occurs via the kidneys as urine. The amount not absorbed from the gastrointestinal tract is excreted in the faeces.

So in summary, taking into account the above mentioned facts, the following absorption rates may be estimated and applied in subsequent risk assessment while performing route-to-route extrapolations:

- Absorption via oral route: 100% (worst case value due to very limited absorption)

- Absorption via inhalative route: 100% (worst case)

- Absorption via dermal route: 10% (borate absorption via skin 0.2%)