Alkaline earth metal and zinc hydroxy(substituted)acetate complexes and alkaline earth metal glyoxylate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

other: expert statement

Adequacy of study:

other information

Study period:

6 April 2020

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The ADME properties are evaluated based on physico-chemical properties and available toxicological data. Additionally, well investigated ADME data on zinc from different sources are taken into account.

Materials and methods

Test guideline

Guideline:

other: ECHA Guidance R.7c

Version / remarks:

June 2017

Test material

Reference

Name:

Unnamed

Type:

Constituent

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Oral absorption
When the registered substance comes into contact with water, they will dissociate immediately into ionic moieties. Thus, absorption via gastrointestinal tract can be carried out by its dissociated products. Physicochemical properties define the absorption behaviour of a chemical. Oral absorption is favoured for molecules with a molecular weight below 500 g/mol. Since the molecular weight of single anions and metal cations is rather low (ca. 200 g/mol and lower) they are expected to be well absorbed via gastrointestinal tract. Also, the high water solubility (> 1000 g/L) and the low logPow (< -2) of the registered substance point to a favoured absorption potential. The anions and metal cations may be taken up also by passive diffusion through aqueous pores of the gastrointestinal epithelial by the bulk passage of water. However, absorption of very hydrophilic substances by passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid. Since the substances are readily biodegradable and are easily oxidized, one may have to consider in addition possible oxidation and degradation products, which are very likely to occur especially during abidance in the stomach or upper GI tract in general after substance application via the oral route.

Zinc is an essential trace element which is regulated and maintained in the various tissues mainly by the gastrointestinal absorption and secretion during high and low dietary zinc intake and because of the limited exchange of zinc between tissues, a constant supply of zinc is required to sustain the physiological requirements. Zinc absorption in the gastrointestinal tract occurs throughout the entire small intestine with the highest rate in the jejunum and the rate of total absorption appears to be concentration-dependent (Lee et al., 1989 cited by RAR, 2004). The zinc absorption process in the intestines includes both passive diffusion and a carrier-mediated process. The absorption can be influenced by several factors such as ligands in the diet and the zinc status. Humans with adequate nutritional levels absorb 20 – 30 % and animals absorb 40 – 50 %. Humans that are zinc deficient absorb more, while persons with excessive zinc intake absorb less (RAR 2004).

In conclusion, as a worst-case assumption the registered substance is considered to be absorbed orally at an amount of 100 %.


Dermal absorption

In order to cross the skin, a compound must first penetrate into the stratum corneum and may subsequently reach the lower layers of the epidermis, the dermis and the vascular network.
The stratum corneum provides its greatest barrier function against hydrophilic compounds, whereas the lower layers of the epidermis are most resistant to penetration by highly lipophilic compounds. Substances with a molecular weight below 100 are favourable for penetration through the skin and substances above 500 g/mol are normally not able to penetrate. The substance must be sufficiently soluble in water to partition from the stratum corneum into the lower parts of the epidermis. Therefore, if the water solubility is below 1 mg/L, dermal uptake is likely to be low.
In general, the dissociated and hence charged constituents will be predominantly present when getting into contact with the moistened skin. Their molecular weights are rather low, which in general indicate a certain potential to penetrate the skin. However, a poor dermal absorption of the registered substance is evident from its very high water solubility. The registered substance has a water solubility of above 1000 g/L. According to ECHA guidance R.7c (ECHA 2017), ‘if water solubility is above 10,000 mg/L, the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Dermal uptake of these substances will be low’.
This is supported by experimental data on soluble zinc compounds. According to RAR (2004), the available information from in vivo as well as the in vitro studies suggests the dermal absorption of soluble zinc compounds through intact skin to be less than 2% (solutions or suspensions).

In conclusion, as a worst-case assumption the registered substance is considered to be absorbed dermally at an amount of 10 %.


Absorption by inhalation

Absorption by inhalation is known to be favourable for small water-soluble substances with high vapour pressure. As the target substance has low vapour pressure and decomposes without melting or boiling at > 221°C, the respiratory absorption as a gas does not have to be regarded.

According to granulometry study results 90 % of the particles of the registered substance are below 15 µm. Particles of this size can reach alveoli. In general, to be readily soluble in blood, a gas, vapour or dust must be soluble in water and increasing water solubility would increase the amount absorbed per breath. However, the gas, vapour or dust must also be sufficiently lipophilic to cross the alveolar and capillary membranes. Therefore, a moderate logPow value (between -1 and 4) would be favourable for absorption. Generally, liquids, solids in solution and water-soluble dusts would readily diffuse/dissolve into the mucus lining the respiratory tract. Hence, with the LogPow of < - 2 at 20°C and the water solubility of > 1000 g/L the potential of absorption via inhalation can be considered as rather high.

With regard to absorption by inhalation of zinc, animal data with various zinc compounds suggest that there is pulmonary absorption following inhalation exposure (RAR, 2004). The absorption of inhaled zinc depends on the particle size and the deposition of these particles. The deposition of soluble zinc compounds occurred mainly in the head region, which is rapidly translocated to the gastrointestinal tract, and much less in the tracheobronchial and pulmonary region that is absorbed locally. Local absorption of the soluble zinc compounds is considered to be approximately 20 % of the material deposited in the head region, 50 % of the material deposited in the tracheobronchial region and 100 % of the material deposited in the pulmonary region. As maximum, the inhalation absorption for the soluble zinc compounds is considered to be 40 %.

In conclusion, taking into account the fraction being able to reach the lower respiratory tract and the hydrophilicity, the potential to be absorbed via the lungs can be estimated as high. Thus, an absorption rate of 100 % is assumed for the registered substances.

Details on distribution in tissues:

Since the registered substance dissociates into ionic moieties before absorption, their distribution and accumulative potential can follow more or less independent ways. Taking into account their rather low molecular weight (< 200 g/mol), hydrophilicity and high-water solubility, their absolute systemic bioavailability is very high, certainly rather in the aqueous compartment and to a lesser extent in fatty tissues.
After oral exposure, the first target will be the gastrointestinal tract, where the substances will be absorbed in high quantities and transferred via the blood stream to the liver. After reaching the liver via the portal vein, the substance will be further distributed via the bloodstream. Here, especially the kidneys due to their filter function and the heart due to its enormous need for nutrients and consequently large blood flow through coronary arteries will be exposed.
Due to the hydrophilicity and small size of the constituents of the registered substance, a possible accumulation can be neglected. Since the solubility and hence absorption via the gastrointestinal tract of the parent compound as well as degradation products is rather complete, a high peak exposure to the compounds and hence high systemic bioavailability can be expected. However, their tendency to be excreted rather fast limits the Area under the curve (AUC).
The affection of the lymphatic system via micellar uptake however is only of minor importance. These conclusions are based on the physico-chemical properties.
With regard to zinc, after absorption zinc ions are primarily bound to albumin in plasma. Then they are transported to the liver before they distribute throughout the body. The normal plasma zinc concentration is ca. 1 mg/L, the total zinc content of the human body (70 kg) is in the range of 1.5-2 g (ATSDR, 1994, cited by RAR, 2004). Zinc is found in all tissues and tissue fluids and it is a co-factor in over 300 enzyme systems. In humans, the major part of total body zinc is found in muscle and bone, approximately 60% and 30%, respectively (Wastney et al., 1986 citied by RAR, 2004). Under normal conditions, the highest zinc concentration per tissue weight is found in bone, hair and in the prostate (Cleven et al., 1993 cited by RAR, 2004).

As a consequence, a wide distribution of the test items throughout the body can be reasonably assumed. There is no potential for bioaccumulation.

Details on excretion:

In general, the major routes of excretion for substances from the systemic circulation are the urine and/or the faeces (via bile and directly from the gastrointestinal mucosa). For non-polar volatile substances and metabolites exhaled air is an important route of excretion. Substances that are excreted favourable in the urine tend to be water-soluble and of low molecular weight (below 300 in the rat) and be ionized at the pH of urine. Most will have been filtered out of the blood by the kidneys though a small amount may enter the urine directly by passive diffusion and there is the potential for reabsorption into the systemic circulation across the tubular epithelium.
The registered substance consists of small hydrophilic ionic moieties. So, a very fast excretion of the compounds via the kidneys and so urine can be expected. Excretion via the gastrointestinal tract (unabsorbed material) and via the bile and consequent subjection to enterohepatic recycling can be neglected.

With regard to zinc ion, within certain limits, mammals can maintain the total body zinc and the physiologically required levels of zinc in the various tissues, constant, both at low and high dietary zinc intakes (RAR 2004).

In humans, the faecal zinc consists of un-absorbed dietary zinc and endogenous zinc from bile, pancreatic juice and other secretions. About 70 – 80 % of the ingested amount of zinc is excreted via faeces (5 to 10 mg/day depending upon the dietary zinc concentration) (Spencer et al., 1966; Venugopal and Lucky, 1978; Reinhold et al., 1991; Wastney et al., 1986, all cited by RAR, 2004) and about 10 % of consumed zinc is excreted in urine.

Applicant's summary and conclusion

Executive summary:

The ADME properties are evaluated based on physico-chemical properties and available toxicological data. Additionally, well investigated ADME data on zinc from different sources (food, medications and other inorganic and organic compounds) are taken into account.

 

Absorption

 

In general, absorption of a chemical is possible, if the substance crosses biological membranes. In case where no transport mechanisms are involved, this process requires a substance to be soluble, both in lipid and in water, and is also dependent on its molecular weight (substances with molecular weights below 500 g/mol are favourable for absorption). Generally, the absorption of chemicals which are surfactants or irritants may be enhanced, because of damage to cell membranes. However, since the registered substance was found to be non-irritating to the skin and eye, the possibility of an enhanced absorption due to damaged cell membranes can be excluded.

 

 

Oral absorption

 

When the registered substance comes into contact with water, they will dissociate immediately into ionic moieties. Thus, absorption via gastrointestinal tract can be carried out by its dissociated products. Physicochemical properties define the absorption behaviour of a chemical. Oral absorption is favoured for molecules with a molecular weight below 500 g/mol. Since the molecular weight of single anions and metal cations is rather low (ca. 200 g/mol and lower) they are expected to be well absorbed via gastrointestinal tract. Also, the high water solubility (> 1000 g/L) and the low logPow (< -2) of the registered substance point to a favoured absorption potential. The anions and metal cations may be taken up also by passive diffusion through aqueous pores of the gastrointestinal epithelial by the bulk passage of water. However, absorption of very hydrophilic substances by passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid. Since the substances are readily biodegradable and are easily oxidized, one may have to consider in addition possible oxidation and degradation products, which are very likely to occur especially during abidance in the stomach or upper GI tract in general after substance application via the oral route.

 

Zinc is an essential trace element which is regulated and maintained in the various tissues mainly by the gastrointestinal absorption and secretion during high and low dietary zinc intake and because of the limited exchange of zinc between tissues, a constant supply of zinc is required to sustain the physiological requirements. Zinc absorption in the gastrointestinal tract occurs throughout the entire small intestine with the highest rate in the jejunum and the rate of total absorption appears to be concentration-dependent (Lee et al., 1989 cited by RAR, 2004). The zinc absorption process in the intestines includes both passive diffusion and a carrier-mediated process. The absorption can be influenced by several factors such as ligands in the diet and the zinc status. Humans with adequate nutritional levels absorb 20 – 30 % and animals absorb 40 – 50 %. Humans that are zinc deficient absorb more, while persons with excessive zinc intake absorb less (RAR 2004).

 

In conclusion, as a worst-case assumption the registered substance is considered to be absorbed orally at an amount of 100 %.

 

 

Dermal absorption

 

In order to cross the skin, a compound must first penetrate into thestratum corneumand may subsequently reach the lower layers of the epidermis, the dermis and the vascular network.

Thestratum corneumprovides its greatest barrier function against hydrophilic compounds, whereas the lower layers of the epidermis are most resistant to penetration by highly lipophilic compounds. Substances with a molecular weight below 100 are favourable for penetration through the skin and substances above 500 g/mol are normally not able to penetrate. The substance must be sufficiently soluble in water to partition from thestratum corneuminto the lower parts of the epidermis. Therefore, if the water solubility is below 1 mg/L, dermal uptake is likely to be low.

In general, the dissociated and hence charged constituents will be predominantly present when getting into contact with the moistened skin. Their molecular weights are rather low, which in general indicate a certain potential to penetrate the skin. However, a poor dermal absorption of the registered substance is evident from its very high water solubility. The registered substance has a water solubility of above 1000 g/L. According to ECHA guidance R.7c (ECHA 2017), ‘if water solubility is above 10,000 mg/L, the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Dermal uptake of these substances will be low’.

This is supported by experimental data on soluble zinc compounds. According to RAR (2004), the available information fromin vivoas well as thein vitrostudies suggests the dermal absorption of soluble zinc compounds through intact skin to be less than 2% (solutions or suspensions).

 

In conclusion, as a worst-case assumption the registered substance is considered to be absorbed dermally at an amount of 10 %.

 

 

Absorption by inhalation

 

Absorption by inhalation is known to be favourable for small water-soluble substances with high vapour pressure. As the target substance has low vapour pressure and decomposes without melting or boiling at > 221°C, the respiratory absorption as a gas does not have to be regarded.

 

According to granulometry study results 90 % of the particles of the registered substance are below 15 µm. Particles of this size can reach alveoli. In general, to be readily soluble in blood, a gas, vapour or dust must be soluble in water and increasing water solubility would increase the amount absorbed per breath. However, the gas, vapour or dust must also be sufficiently lipophilic to cross the alveolar and capillary membranes. Therefore, a moderate logPow value (between -1 and 4) would be favourable for absorption. Generally, liquids, solids in solution and water-soluble dusts would readily diffuse/dissolve into the mucus lining the respiratory tract. Hence, with the LogPow of < - 2 at 20°C and the water solubility of > 1000 g/L the potential of absorption via inhalation can be considered as rather high.

 

With regard to absorption by inhalation of zinc, animal data with various zinc compounds suggest that there is pulmonary absorption following inhalation exposure (RAR, 2004). The absorption of inhaled zinc depends on the particle size and the deposition of these particles. The deposition of soluble zinc compounds occurred mainly in the head region, which is rapidly translocated to the gastrointestinal tract, and much less in the tracheobronchial and pulmonary region that is absorbed locally. Local absorption of the soluble zinc compounds is considered to be approximately 20 % of the material deposited in the head region, 50 % of the material deposited in the tracheobronchial region and 100 % of the material deposited in the pulmonary region. As maximum, the inhalation absorption for the soluble zinc compounds is considered to be 40 %.

 

In conclusion, taking into account the fraction being able to reach the lower respiratory tract and the hydrophilicity, the potential to be absorbed via the lungs can be estimated as high. Thus, an absorption rate of 100 % is assumed for the registered substances.

 

 

Distribution and accumulation

 

Since the registered substance dissociates into ionic moieties before absorption, their distribution and accumulative potential can follow more or less independent ways. Taking into account their rather low molecular weight (< 200 g/mol), hydrophilicity and high-water solubility, their absolute systemic bioavailability is very high, certainly rather in the aqueous compartment and to a lesser extent in fatty tissues.

After oral exposure, the first target will be the gastrointestinal tract, where the substances will be absorbed in high quantities and transferred via the blood stream to the liver. After reaching the liver via the portal vein, the substance will be further distributed via the bloodstream. Here, especially the kidneys due to their filter function and the heart due to its enormous need for nutrients and consequently large blood flow through coronary arteries will be exposed.

Due to the hydrophilicity and small size of the constituents of the registered substance, a possible accumulation can be neglected. Since the solubility and hence absorption via the gastrointestinal tract of the parent compound as well as degradation products is rather complete, a high peak exposure to the compounds and hence high systemic bioavailability can be expected. However, their tendency to be excreted rather fast limits the Area under the curve (AUC).

The affection of the lymphatic system via micellar uptake however is only of minor importance. These conclusions are based on the physico-chemical properties.

With regard to zinc, after absorption zinc ions are primarily bound to albumin in plasma. Then they are transported to the liver before they distribute throughout the body. The normal plasma zinc concentration is ca. 1 mg/L, the total zinc content of the human body (70 kg) is in the range of 1.5-2 g (ATSDR, 1994, cited by RAR, 2004). Zinc is found in all tissues and tissue fluids and it is a co-factor in over 300 enzyme systems. In humans, the major part of total body zinc is found in muscle and bone, approximately 60% and 30%, respectively (Wastney et al., 1986 citied by RAR, 2004). Under normal conditions, the highest zinc concentration per tissue weight is found in bone, hair and in the prostate (Cleven et al., 1993 cited by RAR, 2004).

 

As a consequence, a wide distribution of the test items throughout the body can be reasonably assumed. There is no potential for bioaccumulation for the target and source substances.

 

 

Excretion

 

In general, the major routes of excretion for substances from the systemic circulation are the urine and/or the faeces (via bile and directly from the gastrointestinal mucosa). For non-polar volatile substances and metabolites exhaled air is an important route of excretion. Substances that are excreted favourable in the urine tend to be water-soluble and of low molecular weight (below 300 in the rat) and be ionized at the pH of urine. Most will have been filtered out of the blood by the kidneys though a small amount may enter the urine directly by passive diffusion and there is the potential for reabsorption into the systemic circulation across the tubular epithelium.

The registered substance consists of small hydrophilic ionic moieties. So, a very fast excretion of the compounds via the kidneys and so urine can be expected. Excretion via the gastrointestinal tract (unabsorbed material) and via the bile and consequent subjection to enterohepatic recycling can be neglected.

 

With regard to zinc ion, within certain limits, mammals can maintain the total body zinc and the physiologically required levels of zinc in the various tissues, constant, both at low and high dietary zinc intakes (RAR 2004).

 

In humans, the faecal zinc consists of un-absorbed dietary zinc and endogenous zinc from bile, pancreatic juice and other secretions. About 70 – 80 % of the ingested amount of zinc is excreted via faeces (5 to 10 mg/day depending upon the dietary zinc concentration) (Spencer et al., 1966; Venugopal and Lucky, 1978; Reinhold et al., 1991; Wastney et al., 1986, all cited by RAR, 2004) and about 10 % of consumed zinc is excreted in urine.