Dizinc pyrophosphate

Endpoint summary

Description of key information

In the absence of specific data on the ADME of dizinc pyrophosphate, its physicochemical properties and relevant toxicity data (where available) were assessed for insights into likely ADME characteristics. Since dizinc pyrophosphate will dissociate to Zn²⁺ions and the phosphate group also toxicokinetic information on other zinc compounds were taken into account for the toxicokinetic assessment. Zinc and thus dizinc pyrophosphate is considered to be absorbed via oral and inhalation route. Dizinc pyrophosphate is a solid metal compound and therefore considered to be badly absorbed via dermal route. Once absorbed, zinc is widely distributed throughout the body. Zinc content is highest in muscle, bone, gastrointestinal tract, kidney, brain, skin, lung, heart, and pancreas. In plasma, two-thirds of the zinc is bound to albumin which represents the metabolically active pool of zinc. This pool of plasma zinc is frequently referred to as loosely bound zinc because albumin has the ability to give up bound zinc to tissues. Zinc is excreted in both urine and feces.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

There are no studies available in which the toxicokinetic behaviour of dizinc pyrophosphate (CAS 7446-26-6) has been investigated.

Therefore, in accordance with Annex VIII, Column 1, Section 8.8.1, of Regulation (EC) No 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017), assessment of the toxicokinetic behaviour dizinc pyrophosphate is conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the physico-chemical and toxicological properties according to Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017).

Dizinc pyrophosphate is a solid at 20°C with a molecular weight of 304.76 g/mol and a water solubility of 12.871 mg/L at 20°C. Since dizinc pyrophosphate will dissociate to Zn²⁺ions and the phosphate group also toxicokinetic information on other zinc compounds were taken into account for the toxicokinetic assessment. Toxicokinetic information on zinc are taken from the toxicological profile for zinc (ATSDR).

ABSORPTION:

No data are available on absorption of dizinc pyrophosphate. If no data is available, basic physico-chemical information should be taken into account, i.e. molecular mass and lipophilicity (log P) and water solubility (ECHA, 2017). This current approach to absorption is conceived for organic chemical compounds. However, this approach is not considered particularly relevant for metals, for the following reasons:

 

• log Pow is a parameter that has no bearing whatsoever in the prediction of the properties of a metal or of an inorganic salt of a metal. This has already been recognised for organisms living in the environment, from which organic substances are transferred to biota via passive diffusion as predicted by Fick's Law. In contrast, most inorganic metal species do not permeate the membranes that separate organism from the external environment by passive diffusion. Instead, the uptake of metals largely depends on the presence of specific transport systems that provide biological gateways for the metal to cross the membrane.

 

• Conventional thinking on percutaneous transfer mechanisms assumes that dissolution of a compound is a prerequisite for subsequent (predominantly diffusion controlled) absorption mechanisms to take place. However, the dissolution of an inorganic metal compound or the metal itself on the skin surface will intrinsically require dissociation, and ultimately liberation of free metal cations.

 

• It is therefore obvious that the second criterion for assigning an absorption rate (namely molecular weight) is irrelevant for metals, since under no circumstances is it feasible that any metal cation may exceed the cut-off value of “500“.

Oral:

In several studies oral absorption rates of zinc in humans were measured. Absorption ranged from 8 to 81% following short-term exposures to zinc supplements in the diet; differences in absorption are probably due to the type of diet (amount of zinc ingested, amount and kind of food eaten). The body's natural homeostatic mechanisms control zinc absorption from the gastrointestinal tract. Persons with adequate nutritional levels of zinc absorb approximately 20–30% of all ingested zinc. Those who are zinc-deficient absorb greater proportions of administered zinc. Absorption of zinc occurs from all segments of the intestine, although the largest proportion of zinc absorption occurs from the duodenum. The zinc absorption process includes both passive diffusion and a carrier-mediated process. The intestinal absorption of zinc appears to be a saturable carrier-mediated process at low zinc dose levels involving a cysteine-rich intestinal protein (CRIP).

Inhalation:

According to ECHA (2017) guidance, particles with aerodynamic diameters below 100 µm have the potential to be inhaled. In a recent study report (2016), the mean mass median aerodynamic diameter of dizinc pyrophosphate was measured to be 5 µm. Therefore, dizinc pyrophosphate particles can be inhaled and likely reach the alveolar region of the respiratory tract since they are below 15 µm (ECHA, 2017). Besides, the substance is anorganic and therefore would not have the potential to be absorbed directly across the respiratory tract epithelium. Non-resorbed particles in the oral-nasal cavity, the airways and the lungs will mainly be cleared from the lungs by the mucocillary mechanism and swallowed and thus absorbed there.

Quantitative studies regarding absorption of zinc and zinc compounds after inhalation exposure in humans are limited. The absorption of inhaled zinc depends on the particle size and solubility, both of which may greatly influence the deposition and clearance of zinc aerosols, particularly insoluble zinc oxid. Elevated levels of zinc have been found in the blood and urine of workers exposed to zinc oxide fumes.

 

Dermal:

No data are available on dermal absorption of dizinc pyrophosphate. If no data is available, basic physico-chemical information should be taken into account, i.e. molecular mass and lipophilicity (log P) (ECHA, 2017). Following, a default value of 100% skin absorption is generally used unless molecular mass is above 500 and log P is outside the range [-1, 4], in which case a value of 10% skin absorption is chosen. Due to the special properties of metals and their inorganic salts as explained above should be taken into account while evaluating the dermal absorption rate.

 

Therefore, for dizinc pyrophosphate an approach consistent with the methodology proposed in HERAG guidance for metals is used:

In contrast to the default 10% or 100% values for substances with no further information, the currently available scientific evidence on dermal absorption of metals (predominantly based on the experience from previous EU risk assessments) yield substantially lower values as described subsequently:

Measured dermal absorption values for metals or metal compounds in studies corresponding to the most recent OECD test guidelines are typically 1% or even less. Therefore, the use of a 10% default absorption factor is not scientifically supported for metals. This is corroborated by conclusions from previous EU risk assessments (Ni, Cd, Zn), which have derived dermal absorption rates of 2% or far less (but with considerable methodical deviations from existing OECD methods) from liquid media - more recent and guideline-conform testing with refined accuracy has even yielded dermal absorption rates at or below 0.3% (Cu, Pb, Sb). Thus, on a preliminary basis, currently a default dermal absorption rate of 1% for absorption from liquid aqueous media would appear reasonable and adequately conservative for regulatory purposes based on a comparative assessment of the results from reliable, guideline-conform dermal absorption studies.

However, considering that under industrial circumstances many applications involve handling of dry powders, substances and materials, and since dissolution is a key prerequisite for any percutaneous absorption, a factor 10 lower default absorption factor may be assigned to such “dry” scenarios where handling of the product does not entail use of aqueous or other liquid media. This approach was taken in the EU risk assessment on zinc. A reasoning for this is described in detail elsewhere (Cherrie and Robertson, 1995), based on the argument that dermal uptake is dependent on the concentration of the material on the skin surface rather than it’s mass.

The following default dermal absorption factors for metal cations and thus for Zn²⁺are therefore proposed:

From exposure to liquid/wet media: 1.0%

From dry (dust) exposure: 0.1 %

DISTRIBUTION:

No data are available regarding the distribution and metabolism for dizinc pyrophosphate. Looking at the physical/chemical parameters of dizinc pyrophosphate (MW>100 g/mol, inorganic, slightly soluble) a wide tissue distribution of the substance as such is not assumed (ECHA, 2017). But dizinc pyrophosphate will ionise to phosphate anions and zinc cations. Phosphate is dissolved as ions in blood. Zinc is one of the most abundant trace metals naturally occuring in humans. Zinc which is naturally occurring in the body is found normally in all tissues and tissue fluids and is a cofactor in over 300 enzyme systems. Together, muscle and bone contain approximately 90% of the total amount of zinc in the body (≈60 and 30%, respectively). Organs containing sizable concentrations of zinc are the liver, gastrointestinal tract, kidney, skin, lung, brain, heart, and pancreas. High concentrations of zinc were also detected in the prostate, retina, and sperm. Zinc levels may vary considerably from one individual to another. To some degree, the distribution of zinc in some tissues appears to be regulated by age. Zinc concentrations increase in the liver, pancreas, and prostate and decrease in the uterus and aorta with age. Levels in the kidneys and heart peak at approximately 40–50 years of age and then decline. Zinc is present in blood plasma, erythrocytes, leukocytes, and platelets, but is chiefly localized within erythrocytes (of which 87% is in carbonic anhydrase, the major binding site). Zinc deficiency has been demonstrated to decrease the ability of erythrocytes to resist hemolysis in vitro. This finding suggests that zinc stabilizes the erythrocyte membrane. In plasma, two-thirds of the zinc is bound to albumin; the remainder is bound primarily to α2-macroglobulin. It appears that the limited number of binding sites for zinc in plasma albumin and macroglobulin regulates the amount of zinc retained by the body. Albumin-bound zinc has been correlated with plasma zinc levels, whereas α2-macroglobulin shows no correlation with plasma zinc levels. Hormones, such as the adrenocorticotrophic hormone (ACTH), appear to regulate the concentration of zinc in the liver. ACTH, secreted by the anterior pituitary gland, stimulates the secretion of glucocorticoids. Glucocorticoids, or hormones with glucocorticoid activity, have been shown in vitro to stimulate the net zinc uptake in cultured liver cells and at the same time activate the gene that regulates metallothionein synthesis. However, there are no in vivo data to support these in vitro findings. Metallothionein in the cells of the intestinal mucosa binds zinc, thus regulating its release into the blood. The transfer of zinc across perfused placentas, as found in in vitro studies, is slow; only 3% of maternal zinc has been demonstrated to reach the fetal compartment in 2 hours. The in vitro transfer of zinc between mother and fetus is bidirectional, with binding in the placenta. It is proposed that zinc uptake in the placenta involves a potassium/zinc transport system. Newborns may also be exposed to zinc from their mothers by milk transfer of zinc during lactation.

METABOLISM:

Zinc is not metabolized in the body, but it may be transported or incorporated into complexes or tissues.

EXCRETION:

Limited information regarding zinc excretion following inhalation exposure in humans is available. Workers exposed to zinc oxide fumes had elevated levels of zinc in the urine indicating that this is a route of excretion. The principal route of excretion of ingested zinc in humans is through the intestine. Zinc loss in the body is by secretion via the gut, and the remainder occurs in the urine. Fecal excretion of zinc increases as intake increases. Excretion of zinc in the urine also reflects zinc intake. Minor routes of elimination are saliva secretion, hair loss, and sweat.

Reference:

ATSDR (1994). Toxicological profile for zinc (update). Agency for Toxic Substances and Disease Registry, Atlanta.

Cherrie and Robertson (1995): Biologically relevant assessment of dermal exposure; Ann. Occup. Hyg. 39, 387-392

ECHA (2017): Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c: Endpoint specific guidance, Version 3.0, June 2017

HERAG (2007);HERAG fact sheet - assessment of occumpational dermal exposure and dermal absorption for metals and inorganic metal compounds; EBRC Consulting GmbH / Hannover /Germany; August 2007; http://www.ebrc.de/downloads/HERAG_FS_01_August_07.pdf)