Diamminediisocyanatozinc

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Remarks:

Expert statement

Type of information:

other: Expert statement

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: No GLP-conform guideline study, but scientifically valid expert statement based i.a. on studies assessed with Klimisch 1 or 2

Objective of study:

absorption

distribution

excretion

toxicokinetics

Qualifier:

no guideline required

Principles of method if other than guideline:

An extensive assessment of the toxicokinetic behaviour of Diaminodiisocyanatozinc was performed, taking into account the chemical structure, the available physico-chemical and toxicological data.

GLP compliance:

no

Radiolabelling:

other: not applicable

Species:

other: not applicable

Strain:

other: not applicable

Details on test animals or test system and environmental conditions:

not applicable

Route of administration:

other: All relevant routes of administration are discussed in the expert statement.

Vehicle:

other: not applicable

Details on exposure:

not applicable

Remarks:

not applicable

Control animals:

other: not applicable

Positive control reference chemical:

not applicable

Details on study design:

not applicable

Details on dosing and sampling:

not applicable

Statistics:

not applicable

Type:

absorption

Results:

The relevant absorption rates were estimated to: Oral absorption: approx. 50% Dermal absorption: approx. 10% Inhalative absorption: approx. 100%

Type:

distribution

Results:

Vast distribution of CO2 and NH3 is expected, zinc is distributed when dissolved.

Type:

metabolism

Results:

Metabolism is irrelevant, hydrolysis is the relevant kind of degradation.

Type:

excretion

Results:

A fast excretion of NH3 and CO2 is expected, zinc will be excreted upon a potential retainment in der body similarly.

Details on absorption:

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 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 Diaminodiisocyanatozinc was found to be non-irritating to the skin, the possibility of an enhanced absorption due to damaged cell membranes could be excluded, but the corrosiveness to eyes may leave a remaining risk.
Due to the lack of experimental absorption data, the following physico-chemical parameters of Diaminodiisocyanatozinc will be taken into account when discussing its absorption into the body:
- Molecular weight = 183.5 g/mol
- Water solubility = Unstable in water, solubility was estimated to be approx.10-2g/l
- Vapour pressure = 2 x 10-3Pa at 25°C
- Particle size: 100% of the particles have the potential to be inhaled. Of these, approx. 99% may reach the thoracic region (according to ECHA's former guidance R7.C, 50µm) or approx. 25% (10µm, R7.C of July 2015), and of those of them, which may reach the alveoles, are approx. 50% or approx. 10%, dependent on the guidance

Absorption from the gastrointestinal tract
In the small intestine absorption occurs mainly via passive diffusion or lipophilic compounds may form micelles and be taken into the lymphatic system. Additionally, metabolism can occur by gut microflora or by enzymes in the gastrointestinal mucosa. However, the absorption of highly lipophilic substances (Log Pow of 4 or above) may be limited by the inability of such substances to dissolve into gastrointestinal fluids and hence make contact with the mucosal surface. The absorption of such substances will be enhanced if they undergo micellular solubilisation by bile salts. Substances absorbed as micelles enter the circulation via the lymphatic system, bypassing the liver. Consequently, immediate Cytochrome P450 metabolism is less important here as for substances which directly enter the hepatic system via the portal vein.
According to ECHA’s guidance R.7c [ECHA 2008], it is stated that the smaller the molecule the more easily it may be taken up. Molecular weights below 500 are favourable for absorption. With a molecular weight of 183.5 g/mol, absorption in general can be considered as possible. However, due to the fast hydrolysis, the aqueous insoluble hydrolysis products (zinc hydroxide, oxide and carbonate, very small quantities of residual Zn(NCO)2(NH3)2), and the soluble gases ammonia and carbon dioxide need to be rather regarded. The interim hydrolysis products can be neglected. As stated above, the soluble gases CO2 and NH3 can be neglected, so only ZnO2, ZnCO3, or possibly Zn(OH)2, are relevant. All these salts have in general a low molecular weight, but are considered insoluble, as stated in the hydrolysis report. Zinc carbonate (MW = 125.418) has a solubility of 0.000091 g/100g H2O, zinc hydroxide (MW = 99.424) 0.000042 g/100g H2O, and zinc oxide (MW = 81.408) is stated to be insoluble in water (Lide DR, CRC Handbook of Chemistry and Physics, 90th Edition).
According to literature data, after oral gavage, 48.4±3.0 of ZnCO3 were absorbed via the GI tract in rats [Galvez-Morros M, 1992]. Due to the similarities in molecular weight and solubility, a similar absorption can be assumed for the other two salts. The fact that the substance and/or its hydrolysis products are well absorbed, can be also proven by oral toxicity data, i.e. by the LD50 value (rats) (Males + Females) of 1127 (989-1285) mg/kg bw, or the 13wk study (rats) NOAEL of 10 mg/kg (males) and NOEL of 10 mg/kg (females).
Also, metabolism is not really relevant here. The substance is an inorganic substance and hydrolyses into insoluble salts or soluble gases, which are also found in regular metabolic pathways in the body, as already stated.
Based on the available data, an absorption rate of 50% or less can be estimated, predominantly due to the available absorption data of ZnCO3.

Absorption from the respiratory tract
Concerning absorption in the respiratory tract, any gas, vapour or other substances inhaled as respirable dust (i.e. particle size ≤ 15µm) has to be sufficiently lipophilic to cross the alveolar and capillary membranes (moderate Log Pow values between 0-4 are favourable for absorption). The rate of systemic uptake of very hydrophilic gases or vapours may be limited by the rate at which they partition out of the aqueous fluids (mucus) lining the respiratory tract and into the blood. Such substances may be transported out of the lungs with the mucus and swallowed or pass across the respiratory epithelium via aqueous membrane pores. Lipophilic substances (Log Pow >0) have the potential to be absorbed directly across the respiratory tract epithelium. Any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic compounds (Log Pow >4), particularly those that are poorly soluble in water (1 mg/L or less) that would otherwise be poorly absorbed [ECHA, 2008].
Diaminodiisocyanatozinc has a very low vapour pressure (2 x 10-3Pa at 25°C) and decomposes before boiling, clearly showing that the inhalative absorption as a gas does not have to be regarded. Any potential gas formation does also occur only upon contact with water (CO2 and NH3), as described above, and so hydrolysis products (i.e. here: soluble gases) do not need to be regarded.
However, particle size distribution is relevant here: 100% of the particles have the potential to be inhaled. Of these, approx. 99% may reach the thoracic region (according to ECHA's former guidance R7.C, 50µm) or approx. 25% (10µm, R7.C of July 2015), and those of them, which may reach the alveoles, are approx. 50% or approx. 10% respirable, dependent on the guidance.
So, based on the particle size distribution, 100% of the applied dose would reach the body via inhalation. So only a negligible amount of particles are subject to nasal clearance, and half the particles are subject to tracheobronchial clearance, and another half of the particles are able to reach the alveoli, using a worst case assumption. As a consequence, the fraction potentially reaching the alveolar region of the respiratory tract beyond the bronchi, where no mechanical excretion mechanism as the ciliary movements is available, cannot be neglected, and also the particles just reaching the bronchi may undergo relatively fast hydrolysis / solubilisation, so it needs to be concluded that nearly all particles are bioavailable. Hirano et al. suggested for ZnO instilled into the rat lung that ZnO particles were solubilized in the bronchoalveolar milieu and cleared from the lung with a half-life of 14 h [Hirano S, 1989].
For absorption of deposited material similar criteria as for GI absorption can be applied. ECHA’s guidance Chapter R.8: Characterisation of dose [concentration]-response for human health proposes to use a default factor of 2 in the case of oral-to inhalation extrapolation, which is equivalent to assume 50% absorption for the oral pathway and complete absorption by inhalation.
Due to the high bioavailablility, small molecule size and the described hydrolysis behaviour, it is concluded that this suggestion is reasonable, and an absorption by inhalation of 100% will be assumed.

Absorption after dermal exposure
In order to cross the skin, a compound must first penetrate into the stratum corneum and may subsequently reach the epidermis, the dermis and the vascular network. The stratum corneum provides its greatest barrier function against hydrophilic compounds, whereas the epidermis is 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 are normally not able to penetrate. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Therefore, if the water solubility is below 1 mg/L, dermal uptake is likely to be low. Additionally, Log Pow values between 1 and 4 favour dermal absorption.
Above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake into the stratum corneum itself may be slow. Moreover vapours of substances with vapour pressures below 100 Pa are likely to be well absorbed and the amount absorbed dermally is most likely more than 10% and less than 100 % of the amount that would be absorbed by inhalation. If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration. During the whole absorption process into the skin, the compound can be subject to biotransformation.
In case of Diaminodiisocyanatozinc, an evaporation after skin contact does not need to be regarded due to the low vapour pressure, and hence it can be assumed that the substance will remain on the skin until mechanical removal. Furthermore, since the substance is not a skin irritant, additional absorption-enhancing effects can be disregarded, too.
Due to the moisture of the skin, not only the substance itself, but also the hydrolysis products need to be regarded. With a molecular weight of 183.5 g/mol of the parent compound and even lower ones of the hydrolysis products, in theory a high absorption via the skin and hence a default dermal absorption rate of 100% [ECHA, 2008] could be assumed. However, considering that the substance is unstable in water, its solubility was estimated to be approx. 0.1 g/l and the fact that the hydrolysis products zinc hydroxide, oxide and carbonate are virtually insoluble in water indicate the opposite and are considered to be more important and so, dermal uptake is likely to be low. In addition, dry particulates will have to dissolve into the surface moisture of the skin before uptake can begin [ECHA, 2008].
The acute toxicity data indicate similarly a diminished absorption via the dermal route compared to the oral one. The dermal LD50(rat) was determined to be > 2100 mg/kg, the LD0 ≥ 2100 mg/kg, no clinical signs were detected and no deaths occurred in either male or female rats dosed with the test item. In comparison, oral LD50 were determined to be Males + Females: 1127 (989-1285) mg/kg body weight / Males: 1208 (971-1503) mg/kg body weight / Females: 1052 (1038-1067) mg/kg body weight. Symptoms included death, none of the animals dosed with 1347 or 1901 mg/kg survived day. So a clear route-dependency is obvious.
ECHA’s guidance Chapter R.7c: Characterisation of dose [concentration]-response for human health proposes for substances which do not meet the criteria of MW > 500 and logPow < -1 or > 4, to deviate from the default assumption of 100% dermal absorption, i.e. to set 10-100% by expert judgement based on other relevant data. Therefore, a limited dermal absorption rate can be assumed, most likely about 10%.

Details on distribution in tissues:

Distribution
In general, it can be stated that the smaller the molecule, the wider is its distribution. A lipophilic molecule (Log Pow >0) is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues. It is not possible to foresee protein binding, which can limit the amount of a substance available for distribution. However, due to the low molecular size of the degradation products, which are formed sufficiently fast before the parent compound is available for distribution, it is not expected, and predictions made on the basis of the physico-chemical characteristics of the parent substance may not be applicable.
In case of Diaminodiisocyanatozinc, no quantitative data is available for distribution patterns. Taking into account its low molecular weight of 183.5 g/mol, the hydrophilicity and the even smaller molecular size of its degradation products, a certain distribution in the aqueous environment can be assumed.
After oral exposure, the first target will be the gastrointestinal tract, where the substance and its hydrolysis products possibly will be absorbed and transferred via the blood stream to the liver, which may be however limited due to the insolubility of zinc hydroxide and zinc oxide in water.
In the available OECD 408 study, 100 mg/kg/day led to a reduced body weight gain of both sexes from week 6. At the end of the treatment period increases /in urinary blood, protein and ketones were seen. This is a clear indication for systemic distribution.
First pass metabolism is not considered relevant here due to hydrolysis, and after absorption, the substance and the soluble degradation products 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 affected.
In general, the expected degradation products can be considered max. slightly more hydrophilic due to their minor size, or insoluble. However, the latter will be considered in addition during assessment of Accumulation, although their solubility and hence absorption via the GI tract is expected to be present, but rather limited.

Transfer type:

other: accumulation literature study

Observation:

other: After induction of a remarkable hyperzincemia in rabbits, high concentrations of Zn accumulated in the kidneys, liver, pancreas, and bone but other tissues such as muscle, brain, and testis maintained nearly normal concentrations of Zn.

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.
As stated above, after a prolonged stay in the body, only the hydrolysis products need to be regarded. The soluble CO2 will be exhaled and NH3 will be excreted via the urine. The insoluble hydrolysis products zinc hydroxide (Zn(OH)2), oxide (ZnO) and carbonate (ZnCO3) will be either excreted via the faeces, or, if an uptake after minor solubilisation occurred, will be excreted as zinc ions. Zinc (2+), unless incorporated in the body as stated under Accumulation inthe attachment, is, as an ion, very hydrophilic and can be excreted easily via the urine.
In consequence, a facilitated excretion can be expected.

Metabolites identified:

no

Remarks:

Metabolism is irrelevant in this case.

Details on metabolites:

In the case of Diaminodiisocyanatozinc metabolism is irrelevant. Due to its inorganic character and fast hydrolysis, only the hydrolysis products are considered relevant, see attachment.

See attached expert statement.

Conclusions:

The present expert statement covers all relevant toxicokinetic parameters to assess the behaviour of Diaminodiisocyanatozinc in the body, the available information is sufficient to enable one to perform a proper risk assessment. Hence, no further information needs to be gathered and further studies can be omitted due to animal welfare. In conclusion, the substance has no potential for bioaccumulation.

Executive summary:

In order to assess the toxicokinetic behaviour of Diaminodiisocyanatozinc, the available toxicological and physico-chemical data were evaluated.

The substance resp. its hydrolysis products are expected to be moderately absorbed via the oral route. An oral absorption rate of 50% or less was estimated due to the very low water solubility of the toxicologically relevant hydrolysis products containing zinc.

Based on the particle size distribution, a high proportion of of the potentially released material has the chance to be inhaled. So a complete absorption by inhalation, i.e. 100%, must be assumed.

Due to the high hydrophilicity of the parent compound as well as its hydrolysis products, they are not favourable for dermal absorption. Therefore, a diminished dermal absorption rate can be assumed, approx. 10%.

So in summary, the absorption rates may be estimated to:

-      Absorption via oral route: 50%

-      Absorption via inhalative route: 100%

-      Absorption via dermal route: 10%

Du to the minor molecular weight of 183.5 g/mol of the parent Diaminodiisocyanatozinc, and the even lower MW of its hydrolysis products, a vast further distribution via the bloodstream is expected. The distribution and excretion of the water soluble ammonia and carbon dioxide is expected to occur rather fast, no accumulation can be expected, whereas the distribution of the insoluble zinc salts and further the zinc cation is expected to be slower, both due to the insolubility of the zinc salts as well as the documented accumulation in several organs. This is a required process to maintain normal body functions, normal zinchomeostasisis required for a functional immune system. So the accumulation of zinc, the relevant constituent, is tissue-specific.

No metabolism needs to be taken into account as hydrolysis is the predominant degradation process. Further, Diaminodiisocyanatozinc and its hydrolysis products have a low potential for bioaccumulation, and will be excreted easily.

Description of key information

Expert statement: Diaminodiisocyanatozinc has a minor potential for bioaccumulation. The relevant absorption rates can be estimated by expert judgement to 50% (oral), 10% (dermal) and 100% (inhalation).

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100