Diphosphoric acid, copper salt

Endpoint summary

Description of key information

The pivotal repeated dose study was a 90-day study by the oral route with copper sulphate pentahydrate. In rats and mice, ingestion of copper sulphate pentahydrate produced forestomach lesions that could be to the irritant effects of the compound. The NOAEL for this effect was 16.7 mg Cu/kg bw/day in rats and 97 and 126 mg Cu/kg bw/day in male and female mice respectively. In rats inflammation of the liver was observed. The NOAEL’s for liver and kidney damage were 16.7 mg Cu/kg bw/day in rats. This is the pivotal study and the NOAEL of 16.7 mg Cu/kg bw/day will be used in the risk characterisation.

The inhalation study LOEC is 0.2 mg cuprous oxide/m3, as (non-adverse) effects were seen at this dose. The study NOAEC is >= 2 mg/kg cuprous oxide/m3, the highest dose level tested and based on the lack of findings in the lung weight ratio.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

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

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects at this concentration (NOAEL).

Key result

Dose descriptor:

LOAEL

Effect level:

2 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

gross pathology

histopathology: non-neoplastic

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

2 000 ppm

System:

gastrointestinal tract

Organ:

kidney

liver

stomach

Treatment related:

yes

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

16.7 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

This study is considered to be a reliability 2 study as it has been conducted on an analogous substance and to a method similar to EU Method B.46 and under the conditions of GLP.

System:

gastrointestinal tract

Organ:

kidney

liver

stomach

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

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

Adequacy of study:

key study

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

Key result

Dose descriptor:

NOAEC

Effect level:

>= 2 mg/m³ air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: The highest dose level tested and based on the lack of findings in the lung weight ratio.

Dose descriptor:

LOEC

Effect level:

0.2 mg/m³ air (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Non-adverse effects were seen at this dose.

Key result

Critical effects observed:

no

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

2 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

The quality of the study is considered sufficient for assessment.

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

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

Adequacy of study:

key study

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

Key result

Dose descriptor:

NOAEC

Effect level:

>= 2 mg/m³ air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: The highest dose level tested and based on the lack of findings in the lung weight ratio.

Dose descriptor:

LOEC

Effect level:

0.2 mg/m³ air (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Non-adverse effects were seen at this dose.

Key result

Critical effects observed:

no

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

2 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

The quality of the study is considered sufficient for assessment.

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose toxicity

 

Read-across for the endpoint ‘repeated dose toxicity’ is justified on the following basis; CuPP is an inorganic ionic compound consisting of phosphate anions and copper cations. As phosphate is a natural component of bodily fluids and is not considered to be toxic the copper ion is considered to be the most relevant species for toxicological investigation.

 

Therefore, in order to minimise animal testing, the registrant has utilised available studies on copper sulphate and copper(I) oxide. This approach is supported by the fact that extensive investigations have shown that copper and copper compounds are considered equally or less bioavailable to a number of animal species when compared to copper sulphate, therefore the use of copper sulphate studies in determining the DNEL’s is justified on scientific grounds and will provide a worst-case for the risk assessment.

 

There are many studies in the public domain dealing with the repeat and chronic toxicity of copper compounds to several animal species. However, these studies did not meet the higher quality criteria (1 or 2) under the BPD quality criterion selection and will therefore not be used in the risk assessment and will not be described in this document. However, the VRAR, 2008 provides a full review of these studies and the discussion on the unsuitability/unacceptability of these studies, risk assessment. The studies summarised below have been identified as the pivotal studies in this Section

 

Non human information

 

The NTP study summarised above is considered to be the pivotal study for Cu2+ presented as copper sulphate pentahydrate and results in an NOAEL of 16.7 mg Cu /kg/bw/day in the rat. This study will be used in the subsequent calculation of the dermal DNEL.

 

A chronic study (>= 1 year) is not considered appropriate, as no serious or severe toxicity effects of particular concern were observed in the 90-day study for which the available evidence is adequate for toxicological evaluation and risk characterisation.

 

Repeated dose toxicity: dermal

This study is usually required when the dermal route of exposure is significant and the compound is known to be toxic by the dermal route and can penetrate through intact skin. The need to conduct this study with copper or copper compounds must therefore be considered not necessary as although the dermal route of exposure is the most significant route there is no evidence to indicate that copper or copper compounds can cause toxicity or indeed pass through intact skin at significant levels. Acute dermal toxicity studies showed no toxic effects up to and including the highest dose tested. In addition, CuPP does not induce a skin irritating effect facilitating penetration through the skin. Therefore an accurate and realistic determination of dermal toxicity can be derived from available sub-chronic oral exposure studies, permissible systemic copper levels and in vitro dermal penetration studies on copper and copper compounds.

Repeated dose: inhalation

A GLP-compliant 28 -day repeat-dose inhalation study was conducted in accordance with OECD Guideline 412, with the addition of a 13 -week recovery period and an evaluation of adaptation to test substance exposure (three intermediate time-points at week 0, week 1, and week 2). Further additional study endpoints were measurements of copper levels in lung tissue, lung lavage fluid, liver, brain, as well as wet/dry lung weight ratio and clinical chemistry and cytology of bronchoalveolar lavage fluid of all animals. The additional study endpoints were designed to aid in the interpretation of any test substance effects. The study resulted in the LOEL of 0.2 mg cuprous oxide/m3, as (non-adverse) effects were seen at this dose. The study NOAEL is >= 2 mg/kg cuprous oxide/m3, the highest dose level tested and based on the lack of findings in the lung weight ratio.

Justification for classification or non-classification

Specific target organ toxicity (CLP Regulation) – repeated exposure (STOT RE)

Summary and discussion of Specific target organ toxicity – repeated exposure

Chronic toxicity, oral:

The liver is the critical organ for copper. The high quality repeated dose study in rats (Hebert (1993) - rat ) is retained for assessing classification according to regulation (EC) 1272/2008 as specific target organ toxicant (STOT-RE) –, oral. Classification criteria are not met since no severe adverse effects were observed at the guidance value, oral for a Category 1 classification of 10 mg/kg bw/day and at the guidance value for a Category 2 classification of 100 mg/kg bw/day. No classification required.

Subacute toxicity, inhalation:

No STOT classification is proposed from this study as none of the observed effects were considered severe enough to merit classification by the inhalation route.

Conclusions on classification and labelling

No classification as STOT-RE under regulation (EC) 1272/2008 (EU CLP) is proposed. No classification or SCLs are considered necessary.