Fatty acids, C18-24, zinc salts

Endpoint summary

Description of key information

Data on the toxicokinetics of substance Fatty acids, C18-24, zinc salts are not available. However, upon dissolution, the salt dissociates to release the moieties zinc and fatty acid(s) anions as discrete, solvated species, eg in the gastrointestinal tract. Once dissociated, the moieties are individually processed in the body with distinct kinetics, metabolism and distribution.

Additional information

FATTY ACIDS, C18-24, ZINC SALTS:

Data on the toxicokinetics of substance Fatty acids, C18-24, zinc salts are not available. The European Food Safety Authority (EFSA) Panel in its scientific opinion on fatty acid salts (EFSA, 2018, Re-evaluation of sodium, potassium and calcium salts of fatty acids (E 470a) and magnesium salts of fatty acids (E 470b) as food additives, EFSA Journal EFSA Journal 2018;16(3):5180) considered that sodium, potassium, calcium and magnesium salts of fatty acids are expected to dissociate in the gastrointestinal tract into fatty acid carboxylates and their corresponding cations as far as the salts are dissolved. The same can also be expected for zinc salts of fatty acids. Thus, data on other zinc compounds are used as it is assumed that after intake substance Fatty acids, C18-24, zinc salts is changed (at least in part) to ionic zinc and that only ionic zinc is determining biological activities. The toxic potential of the fatty acids C18-24 is assumed to be negligible. Fatty acids are generally not considered to represent a risk to humans, which is reflected in their exclusion from REACH registration requirements (c.f. REACH Annex V (Regulation (EC) No 987/2008)). Thus, the following read-across concept has been developed:

1. Substance Fatty acids, C18-24, zinc salts is a zinc salt of long-chained fatty acid containing 18-24 C-atoms. Thus, read-across of data available for zinc salts of shorter-chained (C8, C12) and similar-chained (C18, C16-18, C22) fatty acids based on structural similarity, water solubility and zinc content and applying bridging principles in a conservative, worst-case approach is assumed to adequately describe the toxicological potential of substance Fatty acids, C18-24, zinc salts.

2. In order to evaluate toxicological properties of the substance Fatty acids, C18-24, zinc salts, in addition information on the assessment entities zinc cation and fatty acids, C18-24 anions were considered. For a documentation and justification of the assessment entity approach, please refer to the separate document attached to section 13, namely "Read Across Assessment Report for substance Fatty acids, C18-24, zinc salts".

A full read-across of data and conclusions based on zinc content correction and the solubility of substance Fatty acids, C18-24, zinc salts (being slightly soluble/insoluble) is considered. This read-across approach is in accordance with the conclusion on toxicokinetics, metabolism and distribution of a structural analogue (i.e. Fatty acids, C16-18, zinc salts) in EU RAR Zinc stearate (CAS# 91051-01-3, CAS# 557-05-1) Part II – Human Health. EUR 21168 EN, http://echa.europa.eu/documents/10162/08799aec-42c5-44e0-9969-baa022c66db1):

“No data were provided on the toxicokinetics of zinc distearate. Data on other zinc compounds have been used, as the basic assumption is made that after intake all zinc compounds (including metallic zinc) are changed (at least in part) to the ionic species and that it is this zinc cation that is the determining factor for the biological activities of the zinc compounds.

Within certain limits, the total body zinc as well as the physiologically required levels of zinc in the various tissues can be maintained, both at low and high dietary zinc intake. Regulation of gastrointestinal absorption and gastrointestinal secretion probably contributes the most to zinc homeostasis. In spite of this a regular exogenous supply of zinc is necessary to sustain the physiological requirements because of the limited exchange of zinc between tissues.

The Zn²⁺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.

Persons with adequate nutritional levels absorb 20-30% and animals 40-50%. However, persons that are Zn-deficient absorb more, while persons with excessive Zn intake absorb less. For risk assessment, for the more soluble zinc compounds (chloride, sulphate) the lower bound of the absorption range at adequate nutritional levels is taken (i.e. 20%). For zinc oxide it has been shown that bioavailability is about 60% of that for soluble zinc salts, corresponding to 12-18%. For zinc metal, zinc phosphate and zinc distearate no bioavailability data were present. As these forms have limited solubility in diluted acids (stomach) comparable to zinc oxide, for the less soluble zinc compounds (oxide, phosphate, distearate, metal) an oral absorption value of 12% will be taken for risk assessment.

In situations of exposure excess (e.g. in case of high dermal or inhalation exposure at the workplace) the oral uptake of zinc compounds will probably be less than the values taken for risk assessment (20% and 12%). However, as this reduction in uptake is not quantifiable, also for excess exposure situations the same oral absorption values will be applied. Some justification for this approach can be found in the observation that for intake levels differing by a factor of 10, uptake levels vary maximally by a factor of two.

Quantitative data on the absorption of zinc following inhalation exposure (especially relevant in occupational settings) are not available. Some animal data suggest that pulmonary absorption is possible. In animal studies on zinc oxide retention in the lungs half-life values of 14 and 6.3 hours were reported for dissolution. As the absorption of inhaled zinc depends on the particle size and the deposition of these particles, data were provided on the particle size distribution ofzinc aerosol in three different industry sectors. When analysing the particle size distribution data with a multiple path particle deposition (MPPDep) model, it appeared that for zinc aerosols the largest part of the deposition takes place in the head region and much less in the tracheobronchial and pulmonary region. Although most of the material deposited in the head and tracheobronchial region is rapidly translocated to the gastrointestinal tract, a part will also be absorbed locally. Based on data for local absorption of radionuclides in the different airway regions, it is assumed that local absorption for the soluble zinc compounds will amount to 20, 50 and 100% of the material deposited in head, tracheobronchial and pulmonary region, respectively. For the less soluble/insoluble zinc compounds negligible absorption is assumed for head and tracheobronchial region and 100% absorption for the pulmonary region. The remaining part of the material deposited in the different airway regions will be cleared to the gastrointestinal tract where it will follow oral uptake kinetics, hence the oral absorption figures can be applied. Applying the above mentioned assumptions to the deposition fractions as determined by the MPPDep model, inhalation absorption for the soluble zinc compounds (zinc chloride and zinc sulphate) is at maximum 40%, while for the less soluble/insoluble zinc compounds (zinc metal, zinc oxide, zinc phosphate and zinc distearate) inhalation absorption is at maximum 20%. These figures will be taken forward to the risk characterisation as a reasonable worst case, because these figures are thought to cover existing differences between the different zinc industry sectors with respect to type of exercise activities (and thus breathing rate) and particle size distribution.

Adequate quantitative data on the absorption of zinc following dermal exposure (relevant in both occupational and consumer settings) are not available. The human data presented are not considered valid, mainly since either wounded skin was investigated, or suction blisters were raised, impairing the intactness of the skin. Dermal absorption through the intact skin seems to be small (< 2%), based on the results of thein vivoanimals studies as well as thein vitrostudies, but unfortunately shortcomings were noted in allin vivostudies and none of these studies can be used quantitatively. As for thein vitrostudies, it is clear that the % in receptor medium generally gives an underestimation of the % systemically available inin vivostudies. Therefore, the amount detected in the skin should be included as being absorbed by default. This “potentially absorbed dose” more closely resembles the dose becoming systemically availablein vivo.

Zinc bound to or in the skin may become systemically available at a later stage. This can be concluded from results in TPN patients, in which an expected decrease in serum zinc levels with time was counteracted by dermal absorption of zinc to result in steady serum zinc levels. Unfortunately, only 3 of the 6 patients completed the 10-day study period. There are no adequate human data available to evaluate the release of zinc from normal skin following single or repeated dermal exposure, as either blood was sampled for a too short period of time (3 hours; Derry et al., 1983) or the skin was damaged (Agren, 1990, 1991; Hallmans, 1977). Therefore, it can be concluded that following single or repeated dermal exposure zinc can be taken up by the skin, whereas the relevance of this skin depot cannot be judged based on the available data. For example, it is not studied how a large artificial zinc depot in the skin will affect the uptake or homeostasis of other essential ions (e.g. Cu). However, the total database available indicates that skin-bound zinc may not become systemically available in a way that it results in high peak levels of zinc in serum, but rather in a more gradual way. Given the efficient homeostatic mechanisms of mammals to maintain the total body zinc and the physiologically required levels of zinc in the various tissues constant, the anticipated slow release of zinc from the skin is not expected to disturb the homeostatic zinc balance of the body. By expert judgement, based on the aforementioned considerations, the default for dermal absorption of solutions or suspensions of zinc or zinc compounds is therefore chosen to be 2%. Based on the physical appearance, for dust exposure to zinc or zinc compounds a 10-fold lower default value of 0.2% is chosen in the risk assessment.

Zinc is distributed to all tissues and tissue fluids and it is a cofactor in over 200 enzyme systems.

Zinc is primarily excreted via feces, but can also be excreted via urine, saliva, hair loss, sweat and mother milk.“

Please refer to the section for the respective assessment entity for data on the moieties. In brief:

ZINC:

Zinc compounds release, depending on their solubility, zinc cations which determine the biological activity of the respective zinc compounds.

Sufficient data is available on the soluble zinc compounds zinc chloride and zinc sulphate and on the slightly soluble zinc compounds ZnO and ZnCO₃.

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. 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. Persons with adequate nutritional levels absorb 20-30% and animals absorb 40-50%. Persons that are zinc deficient absorb more, while persons with excessive zinc intake absorb less.

For the soluble zinc compounds, the available information suggests an oral absorption value of 20%. This value can be considered as the lower bound range at adequate nutritional levels. The oral absorption of the slightly soluble zinc oxide has been shown to be 60% of that of the soluble zinc compounds. This corresponds to approximately 12-18%. No oral absorption information is available for the remaining slightly soluble and insoluble zinc compounds (i.e., ZnO, Zn(OH)₂, Zn₃(PO₄)₂, ZnCO₃, Zn, ZnS). However, considering that these substances have lower water solubility than ZnO, it can be conservatively assumed that the oral absorption of these compounds is ≤ 12%.

Animal data suggests that there is pulmonary absorption following inhalation exposure. Half-life values of 14 and 6.3 hours were reported for dissolution of zinc oxide. The absorption of inhaled zinc depends on the particle size and the deposition of these particles therefore data was provided on the particle size distribution of zinc aerosol from three different industry sectors. The particle size distribution data was evaluated by using a multiple path particle deposition (MPPDep) model. This model revealed that for zinc aerosols the largest part of the deposition is in the head region and much less in the tracheobronchial and pulmonary region. Although most of the material deposited in the head and tracheobronchial region is rapidly translocated to the gastrointestinal tract, a part will also be absorbed locally.

Based on data for local absorption of radionuclides in the different airway regions, it can be assumed that the local absorption of the soluble zinc compounds will 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. For the slightly soluble and insoluble zinc compounds a negligible absorption can be assumed for materials deposited in the head and the tracheobronchial region. 100% of the deposited slightly or insoluble zinc compounds are assumed to be absorbed in the pulmonary tract. The deposited material will be cleared via the lung clearance mechanisms into the gastrointestinal tract where it will follow oral absorption kinetics. Therefore the inhalation absorption for the soluble zinc compounds is a maximum of 40% and for the slightly soluble and insoluble zinc compounds inhalation absorption is at a maximum of 20%. These values can be assumed as a reasonable worst case, because they are considered to cover existing differences between the different zinc industry sectors with respect to the type of exercise activities (and thus breathing rate) and particle size distribution.

The available information from in vivo as well as the in vitro studies suggests the dermal absorption of zinc compounds through intact skin to be less than 2%. In vitro studies that estimated dermal absorption values only on the basis of the zinc levels in the receptor medium without taking into account the zinc present in the stratum corneum appear to underestimate absorption values derived from in vivo studies. Such zinc trapped in the skin layers may become systemically available at a later stage. Quantitative data to evaluate the relevance of this skin depot are however lacking. Given the efficient homeostatic mechanisms of mammals to maintain the total body zinc and the physiologically required levels of zinc in the various tissues to be constant, the anticipated slow release of zinc from the skin is not expected to disturb the homeostatic zinc balance of the body. Considering the available information on dermal absorption, the default for dermal absorption of all zinc compounds (solutions or suspensions) is 2%. Based on the physical appearance, for dust exposure to zinc and zinc compounds a 10-fold lower default value of 0.2% is a reasonable assumption.

Zinc appears to be distributed to all tissues and tissue fluids and it is a cofactor in over 200 enzyme systems. The excretion of zinc is primarily via faeces, but also via urine, saliva, hair loss, sweat and mothers-milk.

FATTY ACIDS, C18-24:

Fatty acids, C18-24 and their metabolites are assessed not being hazardous to humans. Fatty acids are generally not considered to represent a risk to humans, which is reflected in their exclusion from REACH registration requirements (c.f. REACH Annex V (Regulation (EC) No 987/2008)).

They are naturally structure building part of body lipids and thus main constituent of human and animal cells. As major nutrients, they are readily and extensively absorbed from the gastrointestinal tract. After absorption, fatty acids are either metabolised or incorporated into chylomicrons, which enter the systemic circulation. Ultimately, fatty acids, are either incorporated into glycerides and phospholipids, or catabolised via the β-oxidation pathway and the tricarboxylic acid cycle to carbon dioxide which is finally excreted via exhalation.