Diphosphoric acid, copper salt

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
For further information please refer to read across justification in IUCLID section 13.

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Type:

other: toxicokinetics

Results:

The absorption, distribution and excretion of copper is dependent on the level of copper intake. The toxicokinetic behaviour of several inorganic copper salts is comparable and therefore also applicable to dicopper hydroxide phosphate.

Metabolites identified:

no

Conclusions:

By using a weight of evidence approach it is demonstrated that the absorption, distribution and excretion of copper is dependent on the level of copper intake. Moreover, evaluation of the whole data base reveals that the toxicokinetic behaviour of several inorganic copper salts is comparable and therefore also applicable to dicopper hydroxide phosphate.

Reference 2

Endpoint:

dermal absorption in vitro / ex vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
For further information please refer to read across justification in IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

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Key result

Remarks on result:

other:

Remarks:

By using a weight of evidence approach it is demonstrated that percutaneous absorption of copper is < 6 % of the applied dose independent of the substance applied. Formulations increased the copper concentrations in whole skin.

Conclusions:

By using a weight of evidence approach it is demonstrated that percutaneous absorption of copper is < 6 % of the applied dose independent of the substance applied. Formulations increased the copper concentrations in whole skin. It was considered that the increase in Cu concentration in whole skin may have been due to a build-up of Cu in epidermis, in effect forming a Cu reservoir, followed by slow diffusion through the dermis.

Description of key information

By using a weight of evidence approach it is demonstrated that the absorption, distribution and excretion of copper is dependent on the level of copper intake. Moreover, evaluation of the whole data base reveals that the toxicokinetic behaviour of several inorganic copper salts is comparable and therefore also applicable to Copper (II) pyrophosphate.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Toxicokinetics, metabolism and distribution

 

There is one GLP study according to OECD TG 417 available (Himmelstein, 2003). Within this study it could be demonstrated that several copper salts (copper hydroxide, copper oxide, copper oxychloride, tribasic copper sulphate and Bordeaux Mixture) were similarly absorbed to copper sulphate following oral administration. The absorbed dose ranged from 10.7 to 12.9 % based on percent of the dose measured in whole blood, liver, carcass, bile and urine. The ranking of copper concentrations in excreta and tissue samples was generally faeces > GI tissue and contents (post-biliary) > stomach and contents > liver > bile > plasma ~ whole blood ~ carcass > urine. After termination of the study a complete clearance of administered Cu was observed.

Due to the fact that the water solubility of Copper (II) pyrophosphate is between the water solubility of copper hydroxide and copper sulphate pentahydrate a comparable toxicokinetic behaviour of Copper (II) pyrophosphate is considered.

 

These assumptions are supported by a number of studies which have been performed on analogous substances. These studies are considered to provide useful data for assessing the toxicokinetics of Copper (II) pyrophosphate.

 

Besides the studies available in the IUCLID dossier a Conclusion on the peer review of copper compounds (EFSA Scientific Report(2008) 187, 1-101) is publicly available. The following considerations for copper as a micronutrient are highlighted within this review:

Copper has been the subject of extensive research. It is widely distributed in biological tissues, where it occurs largely in the form of organic complexes, many of which are metalloproteins and function as enzymes. Copper enzymes are involved in a variety of metabolic reactions, such as the utilization of oxygen during cell respiration and energy utilization. They are also involved in the synthesis of essential compounds, such as the complex protein of connective tissues of the skeleton and blood vessels, and in a range of neuroactive compounds concerned in nervous tissue function. Copper is present in almost all foods, most human diets naturally include between 1 to 2 mg/person/day of copper, with some containing up to 4 mg/person/day. Copper levels in blood and tissues are generally stable; the body is able to maintain a balance of dietary copper intake and excretion that allows normal physiological processes to take place. Up to 93 % of the copper in the blood is bound to the enzyme caeruloplasmin, while the majority of the rest are bound to albumin and amino acids; there is strong evidence that absorbed copper is never released free in the blood or in the cells.

A bioequivalence study (Himmelstein, 2003) was performed to compare the five variants of copper, copper hydroxide, copper oxychloride, Bordeaux mixture, tribasic copper sulphate and copper (I) oxide with copper sulphate pentahydrate on bile cannulated rats to demonstrate that toxicological studies on copper sulphate could be used in the toxicological risk assessment of the five variants. Absorption, distribution and excretion rates were similar between the six variants of copper following oral ingestion of 20 mg Cu/kg bw; liver was the principal organ of regulation of copper, and main excretion was via the bile. Liver copper levels increased significantly following dosing with Tmax at 12 hours; depuration was rapid, with levels returning to control by 48 hours after dosing. Plasma concentrations in both control and dosed rats remained unchanged. These findings were consistent with the homeostatic bio-regulation of copper found in the open literature. Oral absorption of copper varies according to the diet; for humans a copper-adequate diet results in 36 % absorption, while a low-copper diet results in 56 % absorption and a high-copper diet in 12 % absorption. Similar figures were found in rat; 50 % oral absorption was considered for this species.

Distribution occurs directly from the intestine to the liver, which controls the distribution of copper to the rest of the body via the bloodstream, bound to caeruloplasmin. Metabolism does not occur. Copper does not accumulate, except in cases of genetic disease or chronic administration of high doses, where copper accumulates in the liver. Excretion is rapid, via the bile, in a trypsin-independent protein fragment, therefore entero-hepatic circulation does not occur. Significant amounts of copper are excreted bound to metallothioneins contained in intestinal brush border cells, sloughed off and lost in faeces; minor amounts are also excreted in urine and from skin and hair.

 

Dermal absorption

By using a weight of evidence approach it is demonstrated that percutaneous absorption of copper containing formulations is very low: 0.1 to 6 % of the applied dose.

 

Besides the studies available in the IUCLID dossier a Conclusion on the peer review of copper compounds (EFSA Scientific Report(2008) 187, 1-101) is publicly available. The following considerations for copper are highlighted within this review:

An in vitro percutaneous absorption study of copper was performed with the five representative variants of copper (I) and (II). However, the study reported that up to 25 tape strips were used to remove the stratum corneum and discarded. Therefore, no information on the amounts present in tape strips was available. The experts agreed to set the dermal absorption as a 10 % conservative default value (for the concentrate and the in-use spray dilution), based on the lack of information on the tape strips amounts and having in mind the relatively low percentage of oral absorption.