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No data were available on the toxicokinetic properties of the registered substance. Data on zinc compounds (mainly zinc chloride and zinc sulphate) and methacrylic acid have been used to deduce the toxicokinetic properties of the substance because the basic assumption is that after intake of the substance, it is mainly transformed into the ionic species and zinc cation and the methacrylic part of the substance are the determining factors of the biological activities of the registered substance.

Much data are available on zinc compounds whereas methacrylic acid toxicokinetic behaviour was derived from related substances such as acrylic acid, esters of acrylic acid, esters of methacrylic acid and methyl methacrylate. These data are well reviewed in the respective European Risk Assessment Reports.

Toxicokinetics of soluble zinc compounds:

Absorption:

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 than persons with excessive Zn intake. 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%).

 

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. 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 of zinc 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.

 

Adequate quantitative data on the absorption of zinc following dermal exposure are not available. The human data available 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 the in vivo animals studies as well as the in vitro studies, but unfortunately shortcomings were noted in all in vivo studies and none of these studies can be used quantitatively. Zinc bound to or in the skin may become systemically available at a later stage but in a 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. Based on these considerations, the default for dermal absorption of solutions or suspensions of zinc or zinc compounds is therefore chosen to be 2%.

 

Distribution:

After absorption from the gastrointestinal tract, Zn2+is bound in plasma primarily to albumin and then transported to the liver and subsequently 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. Zinc is distributed to all tissues and tissue fluids and it is a cofactor in over 200 enzyme systems.

 

Metabolism/excretion:

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

Toxicokinetics of methacrylic acid and methyl methacrylate:

Absorption:

Methacrylic acid is rapidly absorbed in rats after oral and inhalation administration.

 

Only 3% of radiolabeled methyl methacrylate administered by oral route was found in feces which means that it is almost completely absorbed by oral route.

 

In vitro skin absorption studies in human skin indicate that methyl methacrylate can be absorbed through human skin, absorption being enhanced under occluded conditions. However, only a very small amount of the applied dose (0.56%) penetrated the skin under unoccluded conditions.

 

After inhalation exposure to rats 10 to 20% of the substance is deposited in the upper respiratory tract where it is metabolised. Activities of local tissue esterases of the nasal epithelial cells may be lower in man than in rodents.

 

Distribution:

After oral or inhalatory administration, methyl methacrylate is rapidly absorbed and distributed. Tissue distribution of radioactivity after i.v. administration of labeled methyl methacrylate to three rats was studied by whole body autoradiography. Irrespective of the time of sacrifice the greatest concentrations were determined in blood, heart, lungs, liver, kidneys and salivary glands. Some of the radioactivity was located in the seminal vesicles. It was not possible to determine whether the radioactivity in any of the tissues was due to the presence of methyl methacrylate or its metabolites

 

Metabolism/excretion:

There are no studies which specifically address the metabolism of methacrylic acid. However, data are available on methyl methacrylate and as methacrylic acid was shown to be a metabolite of methyl methacrylate, it can be concluded that methacrylic acid metabolism can be deduced from methyl methacrylate metabolism.

 

After oral administration (gavage; 5.7 or 120 mg/kg bw) of radiolabeled methyl methacrylate to Wistar rats, 65% of the dose was exhaled as CO2 within 2 hr, 76-88% within 10 days. Pulmonary excretion of unchanged methyl methacrylate accounted for less than 1.4% of the dose. Metabolites excreted with urine (4.7-6.0%) were methacrylic acid (0.8% of the dose), methyl malonic acid (1.4%), succinic acid (0.2%), 2 minor metabolites co-eluating with β-hydroxyisobutyric acid and methylmalonic semialdehyde. The authors conclude that methyl methacrylate is metabolised via physiological pathways and enters into the citric acid cycle via methylmalonyl-CoA and succinyl-CoA, which is a part of the valine pathway. After a single i.v. administration to rats of 14C-labeled methyl methacrylate (5.7 or 6.8 mg/kg bw) the metabolism and excretion of methyl methacrylate were qualitatively the same as after oral administration. A high-dose orally administered methyl methacrylate was rapidly hydrolysed by esterases and the methacrylic acid concentration in the blood serum reached a very low level after one hour.

In humans, methyl methacrylate has also been shown to undergo hydrolysis to methacrylic acid during hip replacement operations. Circulating levels of methacrylic acid were comparable with those of methyl methacrylate. Five min after the insertion of the bone cement into the femoral cavity both methyl methacrylate and its metabolite methacrylic acid were detected in significant quantities, concentrations of methacrylic acid tending to lag behind those of methyl methacrylate. The authors therefore conclude that the initial step of methyl methacrylate metabolismin vivois hydrolysis to methacrylic acid catalysed by nonspecific serum esterases.

Bratt H, Hathway DE (1977). Fate of methyl methacrylate in rats. Brit. J. Cancer 36, 114-119

Crout DHG, Corkill JA, James ML, Ling RSM (1979). Methylmethacrylate metabolism in man, the hydrolysis of methylmethacrylate to methacrylic acid during total hip replacement. Clin. Orthop. Relat. Res. 141, 90-95.

EU RAR (2002) Methyl methacrylate. Risk assessment report, 1st priority list, Volume 22, European Commission, Institute for Health and Consumer Protection, European Chemicals Bureau.

EU RAR (2002) Methacrylic acid. Risk assessment report, 1st priority list, Volume 25, European Commission, Institute for Health and Consumer Protection, European Chemicals Bureau.

EU RAR (2004) Zinc chloride. Risk assessment report, 2nd priority list, Volume 45, European Commission, Institute for Health and Consumer Protection, European Chemicals Bureau.